Omega-3 polyunsaturated fatty acids in rodent models of breast cancer.

Quantitative increases in certain dietary fats promote mammary tumor growth, but the experimental data indicate that this tumor promoting capability is not equally expressed by all fatty acid families. There is a large body of evidence from experiments using either carcinogen-induced or transplanted animal mammary tumor models, as well as in vitro studies, which demonstrates that the omega-6 polyunsaturated fatty acids (PUFA) promote mammary tumor development more effectively than omega-3 PUFA. These data indicate that increases in the dietary levels of omega-6 PUFA enhance tumor development, while equivalent increases in dietary levels of omega-3 PUFA often delay or reduce tumor development. Several theoretical mechanisms have been proposed for these contrasting results, but as yet, no definitive explanation has been universally accepted.

Dietary omega-3 polyunsaturated fats and breast cancer.

Although early experimental investigations concluded that quantitative increases in dietary fat promote mammary tumor growth, recent studies have indicated that not all fatty acid families equally express this tumor-promoting capability. This article provides an overview of some of the experimental evidence demonstrating that the omega-6 polyunsaturated fats have significantly different mammary tumor-promoting capabilities from those of the omega-3 polyunsaturated fats. Collectively, these data indicate that whereas increasing dietary levels of omega-6 polyunsaturated fatty acids enhances tumor development, equivalent increases in dietary levels of omega-3 polyunsaturated fatty acids delay or reduce tumor development. Some of the theoretical mechanisms proposed for these contrasting results and their supporting experimental data are discussed.

Dietary n-3 (omega-3) polyunsaturated fatty acid effects on animal tumorigenesis.

Environmental variables influence the incidence and expression of disease. Dietary fat is one environmental variable that has been associated experimentally and epidemiologically with alterations in certain types of tumorigenesis. Recently, detailed biochemical analyses have shown that not all fatty acid families possess the same tumor-promoting potential. In general, diets containing high levels of the n-6 polyunsaturated fatty acids have routinely enhanced tumorigenesis in lipid sensitive carcinogen-induced and tumor transplant tumor models, whereas diets with equivalent levels of n-3 polyunsaturated fatty acids have diminished tumorigenesis. At present, there is no definitive biochemical mechanism that fully explains these observations, but several possibilities have been proposed. One of the most attractive of these hypotheses is that each polyunsaturated fatty acid family has an individual effect on eicosanoid metabolism which determines its tumor-promoting potential. Regardless of current uncertainties about mechanisms of action, however, results of numerous animal models affirm the importance of qualitative, as well as quantitative, dietary lipid differences on tumorigenesis. This knowledge strengthens the probability that further advances in our understanding of lipid-tumor interrelationships will have important preventive and therapeutic medical benefits.

Dietary fish lipids do not diminish platelet adhesion to subendothelium.

Clinical trials suggest that dietary fish lipids offer protection against pathologic thrombosis. Measurements of platelet aggregation and bleeding time indicate that these protective effects are mediated in part through alterations of platelet function. We studied the effects of supplementary fish lipids (MaxEPA) on platelet adhesion to arterial subendothelium utilizing a modified Baumgartner flow chamber. Template bleeding times were also performed, and platelet lipid composition was determined by gas chromatographic analysis. The results showed that platelet lipid composition was altered significantly during the study. However, total platelet adhesion to arterial subendothelium was not changed by ingestion of fish lipids during the study period. Bleeding times showed some prolongation in most subjects (range: -1.0 to +6.75 min), with a mean change of +0.75 min. We conclude that, in individuals maintained on ad libitum diets, the supplemental amount of fish oil used in this study was enough to induce a significant alteration in platelet lipid composition, but these changes were unaccompanied by any impairment in the ability of platelets to adhere to subendothelium in our model system.

Adrenal insufficiency. A rare initial sign of metastatic colon carcinoma.

A 75-year-old woman evaluated for "drop attacks" 3 years after anterior resection for colo-rectal cancer developed hyponatremia associated with a morning cortisol of 5.7 micrograms/dl, a plasma adrenocorticotropic hormone level of 319 pg/ml, and an inadequate response to cosyntropin. Computed tomography scan demonstrated bilateral adrenal masses. Fine needle aspiration biopsy of the adrenals revealed adenocarcinoma, histologically similar to her previous colon carcinoma. Addison's disease secondary to isolated colon cancer metastases to the adrenals is rare. Our report represents the first antemortem histologically confirmed diagnosis of this entity. A review of the available literature is presented.

A comparative study between individuals receiving thymic irradiation in infancy and their nontreated siblings: clinical and laboratory thyroid abnormalities.

While impairment of thyroid function has been demonstrated for high-dose external radiation (e.g., for Hodgkin's disease), the long-term functional effects of low-dose external radiation have not been fully explored. One hundred fifty-three subjects with a past history of thymic irradiation during infancy were stratified into three dose levels and compared with 51 nonirradiated subjects from a sibling cohort with respect to previously undiagnosed clinical and laboratory thyroidal abnormalities. There was no apparent association between previous thymic irradiation and mean serum levels of T4, free T4, TSH, or antithyroid antibodies, nor was the prevalence of undetected hypothyroidism or hyperthyroidism significantly altered in the irradiated group. Serum thyroglobulin levels were elevated in subjects with palpable thyroid nodules, all of which occurred in thymic-irradiated subjects. Thus persons who have received low-level external thymic irradiation in infancy should continue to have periodic thyroid examinations, but routine serial measurement of other serum thyroidal parameters does not appear to be indicated.

Hyperthyroidism protects against carbachol-induced bronchospasm.

We studied the effect of increased thyroid function on airway reactivity. Carbachol challenge was performed to assess airway reactivity according to a standardized method. Measurements of forced expiratory volume-1 second (FEV1), specific airway conductance (SGaw), the provocative dose of carbachol for a 20 percent decrease in FEV1 (PD-20) and that for a 35 percent decrease in SGaw (PD-35) were established upon entry when each subject was hyperthyroid, and subsequently, after the subjects had returned to the euthyroid state. It was concluded that hyperthyroidism reduced the severity of carbachol-induced changes in airway reactivity as measured by SGaw.

Dietary effects of menhaden oil on the growth and membrane lipid composition of rat mammary tumors.

The objective of this study was to evaluate the effect of quantitative differences in dietary menhaden oil, an n-3 polyunsaturated marine oil, on mammary tumor development and to compare these results with those produced by corn oil, an n-6 polyunsaturated vegetable oil. Inbred female BUF rats were treated with the carcinogen N-methyl-N-nitrosourea (CAS: 684-93-5) and maintained on diets containing graded levels of each of the respective oils. Our results indicated that diets containing 20% menhaden oil produced a reduction in tumor incidence and a prolongation of the tumor latent period. This finding contrasted sharply with the enhanced tumor development and shortened latent period observed in the animals fed the equivalent dietary level of corn oil. Fatty acid analyses performed on the lipids extracted from the tumor and hepatic microsomes of the animals on the menhaden oil diets demonstrated that the proportion of eicosapentaenoic acid (No. of C-atoms:No. of double bonds = 20:5) present in these microsomal lipids was related inversely to mammary tumor development.

Dietary lipid effects on the growth, membrane composition, and prolactin-binding capacity of rat mammary tumors.

The effects of qualitative and quantitative differences in dietary lipid on the growth of N-methyl-N-nitrosourea (CAS: 684-93-5)-initiated mammary tumors were evaluated in inbred female (F344) rats. Specific prolactin-binding measurements and qualitative lipid analyses were performed on both tumor and hepatic microsomes from these animals. Our results indicated that 1) when the polyunsaturated lipid component (corn oil) of the diet exceeded 3%, it was the quantitative level of total lipid, rather than the level of polyunsaturated lipid alone, that best correlated with the observed reduction in tumor latent period; 2) when the polyunsaturated lipid content of the diet fell below 3%, there was a decrease in tumor incidence and an increase in the mean latent period; 3) only those changes in tumor development that occurred when the dietary polyunsaturated lipid content was below 3% were associated with alterations in specific prolactin binding capacity.

Effects of dietary lipids on lactogenic hormone receptor binding in rat mammary tumors.

Both epidemiologic studies in humans and experiments in laboratory animals have indicated that high-fat (HF) diets promote mammary tumor growth; however, the biochemical mechanisms responsible for this accelerated tumor growth are poorly understood; thus this study was designed to determine whether diet-induced alterations in the lipid composition of mammary tumor cell membranes were associated with differences in lactogenic hormone binding capacity. Mammary tumors were induced with N-methyl-N-nitrosourea in 50-day-old female inbred Buffalo rats that were maintained on either HF or low-fat (LF) diets composed of either 20% corn oil or 0.5% corn oil, respectively. The microsome-membrane fractions of these tumors were then analyzed for specific lactogenic hormone binding with the use of 125-I-labeled human growth hormone. Methylated extracts of these same membrane fractions were also subjected to gas-liquid chromatography. Our results demonstrated that the mammary tumor membranes of the HF group did have a significantly greater lactogenic binding capacity than those of the LF group and that these differences in hormone binding were accompanied by significant alterations in the membrane qualitative fatty acid profiles of each group. Therefore, one way in which dietary lipids may be able to influence mammary tumor growth is by modification of the lactogenic hormone binding capacity of tumor cell membranes.

Echocardiographic characterization of the reversible cardiomyopathy of hypothyroidism.

Nineteen patients with untreated hypothyroidism were evaluated by M-mode echocardiography. Asymmetric septal hypertrophy (ASH), defined as a ratio of interventricular septal thickness to left ventricular posterior wall thickness (IVS/LVPW) equal to or greater than 1.3, was identified in 17 cases. Additional abnormalities recognized by echocardiography included reduced amplitude of systolic septal excursion (SSex) [13 patients], reduced per cent of systolic septal thickening (%SST)[19 patients], reduced left ventricular outflow tract dimension (LVOT)[five patients] and systolic anterior motion of the mitral valve (SAM)[five patients]. These findings are similar to some of the echocardiographic features of idiopathic hypertrophic subaortic stenosis (IHSS). In 10 patients who returned to euthyroid state with L-thyroxine therapy, these abnormalities resolved. We conclude that long-standing hypothyroidism leads to a reversible cardiomyopathy, manifested by asymmetric septal hypertrophy with or without other echocardiographic features of a hypertrophic obstructive cardiomyopathy. This previously unrecognized features of hypothyroidism has important diagnostic and therapeutic implications.

Effects of iodine deficiency and high-fat diet on N-nitrosomethylurea-induced mammary cancers in rats.

The effects of an altered content of dietary iodine and fat on the development of N-nitrosomethylurea-induced mammary tumors in rats were studied and correlated with thyroid and pituitary function studies. In three separate experiments, animals fed a semisynthetic diet containing 11.8% fat had an earlier time of tumor appearance and greater tumor burden than did controls maintained on a diet containing 4.6% fat. These diet-associated changes were markedly inhibited by ovariectomy, indicating that the tumor growth was hormone responsive. We examined the possibility that the diet with increased fat content enhanced tumor growth through alterations in prolactin metabolism but could find no consistent elevation in serum prolactin and no increase in pituitary prolactin synthesis in vitro. Our data further showed that rats on an iodine-deficient form of the high-fat diet had no greater tumor growth than did animals receiving an iodine-supplemented form of the same diet. We conclude from these results that iodine deficiency does not promote mammary tumorigenesis. An incidental finding of great interest was that ovariectomy led to a highly significant depression of thyroid-stimulating hormone production in vitro. This suggests that estrogens may directly influence thyroid-stimulating hormone synthesis in vivo and thus contribute to the sex-related differences in thyroid physiology.

Choriocarcinoma with hyperthyroidism: probable identity of the thyrotropin with human chorionic gonadotropin.

A 15-year-old girl developed severe hyperthyroidism secondary to metastatic choriocarcinoma. Her serum contained high levels of human chorionic gonadotropin (HCG) by radioimmunoassay and had a thyroid-stimulating activity different from that of pituitary thyrotropin (TSH) or of long-acting thyroid stimulator (LATS) in the McKenzie mouse bio-assay. Gradient ultracentrifugation localized this thyroid stimulator to a narrow zone midway between markers of transferrin and ovalbumin. On gel filtration it emerged just before albumin as a single peak coinciding with the peak for HCG. Her HCG was identical to an authentic sample of HCG in position to gel filtration columns and on gel electrophoresis. These results suggest that the thyrotropin of choriocarcinoma is HCG.

Studies on the thyroidal defect in an atypical form of Pendred's syndrome.

A 52-yr-old woman and her 47-yr-old brother both had large goiters, short stature, nerve deafness, and mild intellectual impairment. Serum levels of thyroid hormones were normal (sister) on borderline low (brother), urinary 127I levels were normal, and perchlorate discharge tests were negative. After adminstration of 125I, we found normal uptakes and retention of istotope by the thyroid, normal serum half-lives for PB 125I, and absence of labelled iodotyrosines in serum or urine. Particulate fractions from both glands had peroxidase activity by in vitro tests for guaiacol oxidation and tyrosine iodination. Samples from different parts of the sister's gland showed a correlation between peroxidase activity in vitro and radioiodine uptake in vivo. We made three separate preparations of thyroglobulin from the sister and one from the brother by gel filtration on 4% agarose. These were similar to each other and to thyrolobulin samples from normal humans when examined by gel electrophoresis both before and after reduction and alkylation. However, the three thyroglobulins from the same gland differed significantly from one another in their composition of most amino acids. This finding indicates that there can be heterogeneity in the protein portion of thyroglobulin, and since the three samples of thyroglobulin were from the same individual, this heterogeneity was probably not of genetic origin. In these patients we could not demonstrate any of the well-established biochemical defects associated with familial goiter. An abnormality in thyroglobulin structure remains in distinct possibility, but we must defer conclusions until there is more known about thyroglobulin heterogeneity and its relationship to hormone biosynthesis.