Protein C deficiency resulting from possible double heterozygosity and its response to danazol.
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A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function. (+info)
The breast pain clinic: a rational approach to classification and treatment of breast pain.
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Three hundred and fifty women complaining of breast pain symptoms of sufficient severity to interfere with their normal lifestyle were reviewed in a special breast pain clinic over a 5 year period. Seventy-two patients (21%) had spontaneous resolution of breast pain and they required reassurance only before discharge. Of the remaining 278 patients, accurate classification of breast pain syndromes was achieved in 89%, the commonest syndrome being cyclical breast pain which accounted for 54% of the women followed up. The remaining womens' breast pain was classified as trigger zone (14%), continuous (8%), Tietze's disease (5%), spinal root (4%), duct ectasia (4%) and psychological depression (2%). In the remaining 25 patients (9%) the breast pain could not be classified. The experience from this clinic is that a majority of women complaining of severe breast pain symptoms can be accurately classified and appropriate therapy instituted. (+info)
Effects of danazol on mineral homeostasis in normal postmenopausal women: preliminary communication.
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The effects of danazol on calcium homeostasis in normal postmenopausal women was examined in a 14-day study utilizing a dosage of 800 mg per day. Danazol caused significant falls in plasma ionized calcium and in the fasting urinary calcium/creatinine ratio, indicating inhibition of bone resorption. Retention of phosphate was also observed as expected with this anabolic agent. The plasma total alkaline phosphatase was also depressed by the drug, which had no effect on hepatocellular function as measured by plasma AST. Certain effects induced by treatment with danazol were still apparent two weeks after cessation of treatment. The drug was well tolerated and androgenic side effects were not seen. It is suggested that the minimal dose regimen of danazol which exerts a calcium-sharing effect should be identified, and that this regimen should be considered for use in a prospective study of the effects of danazol on bone mineral content in the postmenopause. (+info)
Endocrine-responsive pancreatic carcinoma: steroid binding and cytotoxicity studies in human tumor cell lines.
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We have begun to investigate the steroid responsiveness of pancreatic cancer by comparing human (MiaPaCa, Colo-357, RWP-1, RWP-2) and rodent (AR42j) pancreatic tumor cell lines with cultured estrogen receptor-positive breast cancer cells (MCF-7, T47-D). The four human pancreatic tumors contain measurable levels of specific estradiol binding sites with dissociation constants (Kd) that range from 1 to 9 nM, in contrast to the higher-affinity binding sites measured in the breast cancer cells (Kd less than or equal to 1 nM). Growth of one pancreatic tumor line (MiaPaCa) is stimulated 40% above control by exposure to nanomolar concentrations of estradiol, suggesting that the estrogen receptor in these cells is functioning like that in MCF-7 and T47-D cells. Glucocorticoids (dexamethasone, hydrocortisone) and androgen (fluoxymesterone) stimulate proliferation of Colo-357 cells by as much as 30%. Paradoxically, glucocorticoids inhibit AR42j cells to less than 50% of control growth. Micromolar exposures of estrogen (17 beta-estradiol), antiestrogen (tamoxifen), antiandrogen (dehydroxyflutamide), progestins (progesterone, R5020, medroxyprogesterone acetate), and inhibitors of steroid-metabolizing enzymes (17 beta-N,N-diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one, danazol) impair growth of these pancreatic tumors to varying degrees, and with little relationship to estrogen receptor content. In general, progestins are slightly more growth inhibiting to these pancreatic tumor lines than the other endocrine agents tested, including tamoxifen. Only the RWP-2 cells appear completely resistant to steroidal therapy, showing less than 25% growth inhibition with exposure to therapeutic concentrations (less than or equal to 2.5 microM) of these agents. Colo-357, MiaPaCa, and AR42j cells are most responsive to these endocrine agents, and their overall pattern of sensitivity suggests that the steroid-dependent growth-inhibitory mechanisms of some pancreatic carcinomas may involve both receptor antagonism and direct inhibition of steroidal oxidoreductases. 17 beta-N,N-Diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one, a potent inhibitor of 5 alpha-reductase with minimal affinity for androgen receptor, inhibits growth of Colo-357 cells to less than 40% of control and also inhibits AR42j and MiaPaCa cells. Dehydroxyflutamide, a potent androgen receptor antagonist with no direct influence on 5 alpha-reductase activity, inhibits growth of MiaPaCa and AR42j cells but has no affect on Colo-357 growth.(ABSTRACT TRUNCATED AT 400 WORDS) (+info)
Response of nitrosomethylurea-induced rat mammary tumor to endocrine therapy and comparison with clinical response.
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We have compared the response of the N-methyl-N-nitrosourea-induced rat mammary tumor to various endocrine agents with response in patients with breast cancer. To do this, we have induced tumors in 228 animals (65% of intact rats developed tumors but only 14% of ovariectomized rats developed tumors). In intact rats, 4-hydroxyandrostenedione, tamoxifen, and a combination of tamoxifen, aminoglutethimide (AG), and danazol induced significant tumor regression (P less than 0.001, P = 0.01, P = 0.04, respectively), whereas danazol, AG, and trilostane were ineffective when used singly. Further investigation showed that the inactivity of AG in the rat was due to extensive acetylation of this compound. In order to mimic postmenopausal breast cancer, we ovariectomized rats after N-methyl-N-nitrosourea administration. In ovariectomized animals, AG was again ineffective in inducing tumor regression but 4-hydroxyandrostenedione was highly active when compared to controls (P = 0.002). Comparison with response of this model to endocrine therapy with response in patients indicates that this has good predictive capacity since it shows that agents which have minor activity in human breast cancer such as danazol and trilostane are inactive in the model. The intact rat model does not, however, predict whether a drug will be useful for pre- or postmenopausal patients. We recommend that before committing large numbers of patients to clinical trials on the basis of this model, the metabolism of new compounds should be compared in humans and rats. (+info)
Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia.
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Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia. (+info)
Response of variant hereditary angioedema phenotypes to danazol therapy. Genetic implications.
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Hereditary angioedema (HAE), an auto-somal dominant disorder characterized by attacks of episodic edema is associated with decreased functional levels of the C1 esterase inhibitor. Approximately 85% of patients have lowered antigen levels of a normal inhibitor protein. 15% of patients have normal or elevated antigenic levels of functionless protein. We have examined the response to danazol therapy of patients with the variant HAE phenotypes possessing the abnormal protein in an effort to determine if these patients possess a normal structural C1 inhibitor allele. Four patients with a variant HAE phenotype were treated successfully with danazol. In two patients, distinguished by the presence of a functionless, albumin-bound, C1 inhibitor (phenotype 2), phenotypic analysis of the danazol response by bidirectional immunoelectrophoresis revealed the appearance of the normal C1 inhibitor gene product during danazol therapy. This relatively cathodal C1 inhibitor peak appears in conjunction with the development of nearly normal functional activity. All of the functional C1 inhibitory activity which appeared in the phenotype 2 treatment serum was associated with the electrophoretically normal inhibitor. This normal protein could be separated from the functionless inhibitor protein by immunoadsorption and molecular sieve chromatography. Danazol therapy of the two patients with an electrophoretically normal, functionless C1 inhibitor (phenotype 3) also resulted in a clinical remission associated with development of a significant increment in functional serum C1 inhibitory activity and C1 inhibitor protein. These findings demonstrate that these two HAE phenotypic variants are heterozygous for the normal serum C1 inhibitor, a finding which was not apparent before phenotypic analysis of this serum during danazol therapy. These data provide strong evidence for a basic similarity between the common form of HAE and its phenotypic variants. They also suggest that a structural gene lesion may result in the abnormalities of serum C1 inhibitor function and disease expression in all three of these HAE phenotypes. (+info)
Effect of estradiol and steroid analogues on the clearance of immunoglobulin G-coated erythrocytes.
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Although the disproportionate frequency of several immunologic disorders among women is well recognized, the effect of sex steroids on immunologic processes is unclear. We used an animal model, which has helped to elucidate the effect of corticosteroids in vivo, to quantitatively assess the effect of estradiol and steroid analogues on the immune clearance of IgG-coated erythrocytes. While corticosteroids impaired the clearance of IgG-coated erythrocytes, estradiol, in doses comparable to those achieved during pregnancy, significantly enhanced the clearance. Estradiol, however, did not enhance the splenic clearance of heat-altered erythrocytes. Splenic macrophages isolated from estradiol-treated animals expressed enhanced receptor affinity for the Fc portion of immunoglobulin G [Fc(IgG)], an effect probably responsible for the enhanced in vivo clearance. No consistent effect of estradiol on the splenic macrophage C3 receptors was observed. The synthetic androgen danazol, the mineralocorticoid deoxycorticosterone, and the cortisol metabolite tetrahydrocortisone did not alter the clearance of IgG-coated cells after 7 d of therapy. The estrogen antagonist/agonist tamoxifen enhanced the clearance of IgG-coated cells, but to a lesser extent than estradiol. An effect of estrogens on macrophage Fc (IgG) receptor-mediated clearance may explain in part the variation in clinical expression of several autoimmune disorders during changes in hormonal state, such as pregnancy. (+info)