Monoclonal antibodies to lutropin: are our immunoassays too specific?
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Antibodies, Monoclonal↗
Biomedical subjects
L M Demers
Publications and source records attributed to L M Demers.
Somatostatin analogues in the treatment of breast and prostate cancer.
Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201-995 (Sandostatin R) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.
Antineoplastic Agents↗
A phase I trial of CGS 16949A. A new aromatase inhibitor.
CGS 16949A is a new, nonsteroidal competitive inhibitor of the aromatase enzyme. In this Phase I trial, 16 heavily pretreated postmenopausal patients with metastatic breast cancer were treated with escalating doses of CGS 16949A from 0.6 to 16 mg total daily oral dose. No hematologic, biochemical, or significant clinical toxicity was encountered. Endocrinologic and pharmacologic data were available from 12 of these patients. Maximum inhibition of estrogen biosynthesis was observed at a dose of 2 mg CGS 16949A daily. At this dose, the inhibition of estrogen biosynthesis was equivalent to 1000 mg aminoglutethimide (AG). The fall in plasma and urinary estrogens without a concomitant drop in androgens confirmed the specific blockade of aromatase activity. At doses of 4 to 16 mg daily, CGS 16949A appeared to inhibit the C21-hydroxylase enzyme as well. The t1/2 of CGS 16949A in the circulation was 10.5 hours. Of 16 evaluable patients there were two partial responses and seven patients with stable disease.
Adult↗
Prostaglandin production in chronic progressive multiple sclerosis.
Peripheral blood monocytes have been implicated in the immune reactions that accompany demyelination in patients with multiple sclerosis (MS). We measured prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) release from peripheral monocytes exposed in vitro to complement. Our studies suggest that there is a significantly higher production of PGE2 in monocytes from patients with chronic progressive MS than in those with exacerbation or remitting MS and healthy controls. No significant differences in TxB2 release were noted between the three groups.
Chromatography, High Pressure Liquid↗
Evidence of heterogeneous mechanisms in lipoprotein lipid alterations in hyperandrogenic women.
Fifty-one hyperandrogenic women had their lipoprotein lipid profiles determined. Free and albumin-bound testosterone was associated with triglycerides and with high-density lipoprotein cholesterol independent of fasting insulin levels, percent ideal body weight, and waist/hip ratio. To gain insight into mechanisms of these lipid alterations, the women were subgrouped according to apparent source of androgen excess. Whereas all groups had low levels of high-density lipoprotein-2 cholesterol and high triglyceride concentrations, only in those with high luteinizing hormone-to-follicle-stimulating hormone ratios was free and albumin-bound testosterone associated with triglycerides and high-density lipoprotein cholesterol independent of fasting insulin levels. Relationships between percent ideal body weight and waist/hip ratios, free and albumin-bound testosterone, sex hormone binding globulin, fasting insulin and 2-hour insulin levels and blood pressure are not significant in all subgroups, suggesting differing endocrinological influences and differing mechanisms for lipoprotein lipid alterations.
Adult↗
Eicosanoid production and transfer in the placenta of the diabetic pregnancy.
The metabolism of arachidonic acid (AA) and the transfer of its metabolites was determined in in vitro perfused placental tissue from normal pregnancies and those complicated by maternal insulin-dependent diabetes mellitus (IDDM). 14C-labelled AA was recirculated in the fetal circulation for 60 min while 3H-AA was recirculated in the maternal circulation. Placental effluent was subjected to high performance liquid chromatography (HPLC) and analysis of dual-label scintillation counts. Placentae from IDDM pregnancies converted 3-6 times more radiolabelled AA to eicosanoids than did normal placentae. In addition, the transfer of eicosanoids into the opposing circulation was doubled in placentae from IDDM pregnancies compared to normal placentae. The predominant direction of eicosanoid transfer in both groups of placentae was in the fetal-to-maternal direction. The relative amounts of eicosanoids produced was also altered in placentae from IDDM pregnancies. Increased amounts of thromboxane (Tx) B2 and hydroxyeicosatetraenoic acids (HETEs) were present in both circulations of placentae from IDDM pregnancies. Levels of 6-keto prostaglandin F1a (6KPGF1a) were significantly reduced in both circulations in placentae from IDDM pregnancies. Thus, the ratio of TxA2 to PGI2 and the ratio of HETEs to PGI2 were both significantly increased in placentae from IDDM pregnancies. These results suggest an imbalance in eicosanoid production which may be relevant to abnormal placental structure and function in IDDM pregnancies.
6-Ketoprostaglandin F1 alpha↗
Effect of in vivo coal dust exposure on arachidonic acid metabolism in the rat alveolar macrophage.
Oxygenated metabolites of arachidonic acid (AA) are produced by the alveolar macrophage (AM) and have been shown to mediate inflammatory reactions. We therefore assessed the production of eicosanoids by AM harvested from the lungs of rats exposed to a bituminous coal dust for 2 wk in an inhalation chamber in order to determine if AA metabolism was altered in a manner that may promote an inflammatory response in the lung. Exposure to coal dust resulted in a 66% increase in the number of AM harvested, an increase in thromboxane A2 (TxA2) and leukotriene B4 (LTB4) production to 222% and 181% of control values, respectively, and a decrease in prostaglandin E2 (PGE2) production to 62% of control values. In AM harvested from rats allowed to breath clean air for 2 wk following coal dust exposure, PGE2 production returned to control levels but TxA2 and LTB4 production remained elevated. The TxA2 synthesis inhibitor UK 38,485 reduced TxA2 production in dust-exposed AM both immediately and 2 wk following exposure. Thus, exposure of rats to coal dust significantly alters the metabolism of AA in AM, with potentially important aspects of AA metabolism remaining altered even after a 2-wk recovery period. Based on the established role of eicosanoids in inflammatory and fibrotic processes, these results suggest that the alteration of AM eicosanoid production as a result of the inhalation of coal mine dust may be an important factor in the pathophysiology of coal workers' pneumoconiosis.
Animals↗
Neuroendocrine and gastric myoelectrical responses to illusory self-motion in humans.
We compared gastric myoelectrical activity and endogenous neuroendocrine responses in subjects with and without motion sickness elicited by illusory self-motion or vection. Rotating a drum with black and white vertical stripes around seated stationary subjects (n = 22) produced vection. Gastric myoelectrical activity was recorded with cutaneous electrodes. Thirteen subjects developed gastric dysrhythmias [4- to 9-cycles/min (cpm) signals] and motion sickness during vection, whereas nine subjects maintained normal 3-cpm gastric rhythms and remained symptom free. Base-line plasma cortisol and beta-endorphin levels were significantly greater (P less than 0.01) in the subjects who would develop gastric dysrhythmias and nausea compared with the subjects who would not develop motion sickness. Norepinephrine levels increased in the nauseated group immediately after vection ceased (354.6 +/- 41.1 pg/ml) compared with the symptom-free subjects (223.1 +/- 22.8 pg/ml, P less than 0.05). Epinephrine increased significantly (P less than 0.05) after vection only in the nauseated subjects, whereas dopamine levels were not altered by vection in either group. We conclude that 1) anticipatory increases in plasma cortisol and beta-endorphin occurred in subjects who would develop nausea and gastric tachyarrhythmias during vection; 2) endogenous epinephrine and norepinephrine were increased in subjects who had vection-induced nausea and gastric dysrhythmias; and 3) vection stimulates brain-gut interactions, resulting in gastric tachyarrhythmias and complex neuroendocrine responses in subjects with motion sickness.
Adult↗
Alterations in transfer and lipid distribution of arachidonic acid in placentas of diabetic pregnancies.
Placental tissue from nondiabetic term pregnancies and pregnancies complicated by maternal insulin-dependent diabetes mellitus (IDDM) was perfused in vitro to compare the transfer and lipid distribution of arachidonic acid (AA). Radiolabeled albumin-bound AA was administered into the maternal afferent circulation, and samples of fetal and maternal effluent were collected at 10-min intervals. Perfused placental tissue was collected at the end of each experiment. The effluent was analyzed for total radioactivity, and extracts were subjected to thin-layer chromatography for the assessment of radioactivity associated with various lipid fractions. Placental AA uptake was significantly increased in perfused tissue from diabetic pregnancies (0.88 vs. 1.72 nM.min-1.g-1 in nondiabetic and IDDM, respectively; P less than 0.01), as was AA transfer (0.22 vs. 0.42 ml/min in nondiabetic and IDDM, respectively; P less than 0.01). However, transfer of the highly diffusible marker substance antipyrine was significantly reduced in IDDM placentas (1.79 vs. 2.49 ml/min in IDDM and nondiabetic, respectively; P less than 0.01). Compared with nondiabetic placentas, incorporation of AA into triglyceride was significantly increased in both maternal and fetal effluents and in placental tissue from IDDM pregnancies, whereas the percentage of AA remaining unesterified was reduced in both placental tissue and fetal effluent. Incorporation of AA into phosphoglycerides was significantly reduced in placental tissue but increased in fetal effluent in placentas from IDDM pregnancies. The results of these studies suggest that transfer and lipid distribution of AA are significantly altered in placentas from IDDM pregnancies. These findings may be relevant to the increased incidence of abnormal fetal growth and development associated with IDDM pregnancies.
Arachidonic Acids↗
The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis.
The family of cytochrome P450 enzymes that mediates steroid hydroxylations are distinct but structurally related proteins. Inhibitors of these steroidogenic steps generally exhibit only relative and dose-related specificity. We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer. While a relatively specific aromatase inhibitor at daily dosages of 1-2 mg, CGS 16949A significantly blunted cortisol responses to ACTH at a dose of 16 mg daily. To further evaluate other inhibitory effects of this drug, we determined blood levels of aldosterone (ALDO) and 18-hydroxycorticosterone and their respective urinary metabolites, tetrahydroaldosterone and tetrahydro-18-hydroxy-11-dehydrocorticosterone in 16 postmenopausal women receiving CGS 16949A. At a dose of 16 mg/day, CGS 16949A produced significant (P less than 0.001) suppression of both basal and ACTH-stimulated ALDO production. This was accompanied by a significant rise in the blood 18-hydroxycorticosterone/ALDO ratio (11.4 +/- 0.19; normal, less than 2; P less than 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 +/- 1.2; normal, less than 5; P less than 0.001) in the urinary tetrahydro-18-hydroxy-11-dehydrocorticosterone/tetrahydroaldosterone ratio was also observed. These results suggest that CGS 16949A is a potent inhibitor of the corticosterone methyloxidase type II enzyme at a dose of 16 mg daily. At doses of 1-2 mg daily, CGS 16949A blocks aromatase without altering basal aldosterone production and, thus, exhibits dose-related specificity.
18-Hydroxycorticosterone↗
Thromboxane in cardiovascular disease.
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Blood Preservation↗
Thyroid dysfunction in elderly hospitalized patients. Effect of age and severity of illness.
To investigate the relative effects of aging and severity of illness on thyroid function as well as the prevalence of thyroid dysfunction in the elderly, we performed thyroid function testing on 190 hospitalized patients 60 years of age or older. Abnormalities of thyroid test results were frequent, and only 27% of patients had normal values for all thyroid function studies. The largest number of patients (125) had a low serum T3 level. Regression analysis showed that severity of illness was a stronger predictor of the T3 level than was age. Our results confirm previous observations that clinical thyroid disease in the hospitalized elderly is not uncommon and often goes unrecognized. Our results also demonstrate for the first time that low concentrations of T3 correlate with a quantitative measure of the severity of illness but only marginally with aging.
Age Factors↗
Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgen.
Concentrations of triglycerides are increased and concentrations of high-density lipoprotein (HDL) cholesterol are low in women with hyperandrogenism. These alterations could be related to excessive androgen or estrogen, to hyperinsulinism, or to a combination of these abnormalities. We examined their independent influences on lipids in 21 women with hyperandrogenism, subgrouped according to apparent source of androgen excess. Results for lipid, androgen, and insulin did not differ among subgroups, so these data were pooled. Free plus albumin-bound testosterone (uT) was correlated with triglycerides (r = 0.69, P less than 0.01) and HDL cholesterol (r = -0.56, P less than 0.01). Both triglycerides (r = 0.66, P less than 0.01) and HDL cholesterol (r = -0.48, P less than 0.05) were also correlated with insulin measured during fasting. Partial correlation revealed that, after adjusting for insulin, lipids were associated with uT. This suggests that androgen excess is independently related to lipid excess. Insulin also was correlated with lipids when adjusted for uT. Free plus albumin-bound estradiol was not associated with any of the lipids. We conclude that altered lipids in women with hyperandrogenism result from the independent effects of androgen and insulin.
Adult↗
Differential effects of gonadal function on bone histomorphometry in male and female rats.
The effects of castration on bone histomorphometry and mineral homeostasis were compared in male and female rats. Measurements were performed 4 weeks after sham operation or gonadectomy. Orchiectomy produced increases in serum calcium and decreases in serum testosterone and androstenedione, whereas ovariectomy produced decreases in serum estradiol and testosterone. Orchiectomy did not alter static bone histomorphometric measurements of the tibial diaphysis, whereas ovariectomy increased cross-sectional and medullary areas, lowered endosteal tetracycline-labeled surface length, and markedly increased endosteal nonlabeled surface length. Orchiectomy decreased mean periosteal bone formation rate and mean periosteal bone apposition rate, whereas ovariectomy increased both measurements. Orchiectomy and ovariectomy markedly diminished trabecular area and trabecular surface length at the tibial metaphysis. Orchiectomy did not alter the number of osteoclasts per mm trabecular surface or the percentage of trabecular surface covered by osteoclasts, whereas ovariectomy increased both measurements. These findings indicate that gonadal hormones produce separate and distinct effects on bone metabolism as determined by histomorphometry in male and female rats.
Animals↗
Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer.
In this pilot clinical trial conducted in 10 postmenopausal women with advanced breast cancer, we evaluated the endocrine effects and toxicity of combined somatostatin analog and dopaminergic therapy in the attempt to suppress both growth hormone (GH) and prolactin (PRL) secretion. The patients' mean age was 63 years (range: 54-77) and the average number of previous treatments was 4.8 +/- 2 (SD). All patients were treated with the somatostatin analog SMS 201-995 (100-200 micrograms s.c. in a.m. and h.s.) and bromocriptine (2.5 mg orally twice a day). During treatment, GH levels following provocative testing (either L-DOPA or insulin-induced hypoglycemia) were suppressed in 7/9 patients. Basal somatomedin-S (Sm-C) levels declined in 6/9 women. Both GH and Sm-C levels decreased in 4 patients, while in the remaining 5 only one of the two parameters was lowered on treatment. PRL secretion (during provocative TRH testing) was almost totally abolished in 8/9 patients. The treatment did not affect circulating levels of FSH, LH, E1, E2, E1-S, T4, T3RU, or cortisol. Seven patients experienced no side effects. Nausea occurred in 3, but was severe enough in only one to require discontinuation of therapy. One patient experienced disease stabilization consisting of less than 50% regression of skin nodules and pleural effusion, a decline in CEA titer, and an improved performance status lasting 7 months. We conclude that combined SMS 201-995 and bromocriptine therapy is safe and frequently suppresses GH and PRL secretion. Its role in the treatment of metastatic breast cancer should be tested in patients with less advanced disease.
Aged↗
Mechanism(s) by which activation of protein kinase C is coupled to prostacyclin synthesis in granulosa cells.
We examined the mechanisms by which the phospholipid-sensitive, calcium-dependent protein kinase (protein kinase C) regulates prostacyclin synthesis by ovarian cells. In monolayer cultures of swine granulosa cells, specific phorbol esters significantly augmented production of the stable immunoreactive metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha by 3- to 8-fold. These stimulatory actions were dose (0.03-30 ng/ml) and time (24-96 h) dependent, could be reproduced by non-diterpene activators of protein kinase C, and were corroborated by high performance liquid chromatography and mass spectrometry. The rank order of potency of phorbol esters was 12-O-tetradecanoylphorbol 13-acetate (TPA) greater than phorbol 12,13-dibenzoate greater than phorbol 12,13-dibutyrate greater than pure phorbol base. TPA enhanced de novo synthesis of prostacyclin, and synergized with the divalent cation ionophore, A23187. Although prostacyclin synthetase activity was not induced, microsomal cyclooxygenase activity was significantly increased by phorbol treatment. Moreover, TPA doubled the intracellular accumulation of free arachidonic acid. An inhibitor of phospholipase A2 (quinacrine 100 microM) impeded, whereas melittin (0.01 microM), an activator of cellular phospholipase A2, and purified bacterial phospholipase A2 (5 and 50 mU/ml) both augmented prostacyclin production. RH 59022 (30 microM), an inhibitor of diacylglyceride lipase, also suppressed prostacyclin synthesis. We conclude that the protein kinase C effector pathway is functionally coupled to de novo prostacyclin production in the swine granulosa cell. Increased eicosanoid synthesis can be accounted for by enhanced phospholipase A2 and diacylglyceride lipase-mediated availability of arachidonic acid substrate and an activated cyclooxygenase enzyme without a change in prostacyclin synthetase activity.
6-Ketoprostaglandin F1 alpha↗
Determination of peak trabecular bone density: interplay of dietary fiber, carbohydrate, and androgens.
To elucidate mechanisms linking nutrition and sex hormones to magnitude of peak trabecular bone density, we studied 11 normal women aged 19-21 y. Trabecular bone density was related inversely to dietary fiber (r = -0.69, p = 0.02) and carbohydrate (r = -0.70, p = 0.02) and directly to serum free-and-albumin-bound testosterone (fab T) (r = -0.70, p = 0.02) and total testosterone (total T) (r = 0.66, p = 0.03). Dietary fiber was correlated negatively with fab T (r = -0.74, p = 0.009), total T (r = -0.70, p = 0.02), and androstenedione (Adione) (r = -0.72, p = 0.01). Controlling for the effect of fab T or Adione weakened the relationship between dietary fiber and bone density and the relationship was no longer statistically significant. Conversely, controlling for sex hormones did not abolish the effect of carbohydrate on bone density. The contributions of fab T and carbohydrate to bone density were independent. These results suggest that dietary fiber may depress serum androgens which in turn decrease trabecular bone density. Carbohydrate may also depress bone density but independently of sex steroid hormones.
Adult↗
Inhibition of aromatase with CGS 16949A in postmenopausal women.
Potent, specific, and nontoxic inhibitors of aromatase would be useful for experimental studies and for use in the treatment of breast cancer and other disorders. We evaluated the effects of CGS 16949A, a nonsteroidal inhibitor of aromatase activity, in 12 postmenopausal women with breast cancer by measuring plasma and/or urinary androgens and estrogens after oral administration of CGS 16949A at doses ranging from 0.6-16 mg daily; each dose was given for 2 weeks. The 0.6-mg daily dose partially lowered estrogen levels, and maximum reduction occurred at doses of 2-16 mg daily. The fall in plasma and urinary estrogens without a concomitant fall in plasma androgens confirmed the blockade of aromatase activity. The degree of estrogen reduction was greatest for urinary estrone [to 27 +/- 3% (+/- SE) of basal], followed in order by plasma estrone sulfate (30 +/- 4%), plasma estrone (32 +/- 6%), urine estradiol (45 +/- 5%), and plasma estradiol (65 +/- 5%). Use of gas liquid chromatography-mass spectrometry techniques revealed similar patterns of reduction in catechol estrogens, estriol, and total urinary estrogens, suggesting that CGS 16949A does not alter the pathways of estrogen metabolism. The degree of estrogen reduction was remarkably similar to that caused with aminoglutethimide. At doses of 4-16 mg daily, CGS 16949A inhibited the C21-hydroxylase enzyme as well, based on concomitant rises in plasma androstenedione, testosterone, and 17 alpha-hydroxyprogesterone. This effect was insufficient to lower urinary cortisol excretion during the study. However, a statistically significant blunting of plasma cortisol responses to ACTH occurred with the 16-mg daily dose. No changes in plasma dehydroepiandrosterone sulfate levels or in thyroid, hematological, liver, or renal parameters were found. No significant side-effects of the medication were encountered. CGS 16949A appears to be a specific inhibitor of aromatase at doses below 4 mg daily and to lack apparent side-effects or toxic actions at doses up to 16 mg daily. This agent shows promise as a potent aromatase inhibitor for physiological and clinical studies.
Administration, Oral↗