Biomedical subjects
Publications and source records attributed to L M Berstein.
The structure, properties and therapeutic effect of a synthesized progestin--megestrol acetate (Megace) are discussed. It is most useful in the management of local and metastatic tumors of the breast and endometrium as well as anorexia-cachexia syndrome. It is suggested that other applications in hormone therapy and new ways of avoiding untoward side-effects (weight gain) may be found.
The contribution made by adjuvant hormone therapy in the development of primary multiple endometrial adenocarcinoma (EA) in patients with breast tumors (BT) is not quite clear. The study was based on the data on 5,790 cases of BT treated at our Clinic and 4,447 females screened for hormone-dependent neoplasms. Patients with BT were found to be at high cumulative risk for endometrial carcinogenesis caused by general factors of risk and pathogenesis. The risk was particularly high in BT (stage 1) within 12 months after treatment. There was no correlation between tamoxifen treatment and significant increase in EA frequency. Promotion of tumor proliferation by tamoxifen was identified in endometrial tissue in 62 patients with BT. This may facilitate clinical manifestations of another latent EA in such patients. Dynamic surveillance of the endometrium and ovary should include ultrasonography of pelvic organs and cytologic examination (smears) of the ecto- and endocervix and endometrial aspiration biopsy.
The results of an evaluation of thyroid homeostasis in 54 patients with thyroid cancer (TC), 12-thyroid adenoma (TA), 10-non-toxic nodular goiter (NTG) and 39 healthy controls are discussed. It was demonstrated that assays of blood serum levels of thyrotropic hormone (TTH), thyroxin (T4), triiodothyronine (T3) and thyroglobulin (TG) are useless in diagnosing TC. However, it was confirmed that routine assays of blood serum-TTH, T4 and T3 levels are needed to evaluate the effect of post-operative substitution hormone therapy. Furthermore, the presence of recurrence or metastasis was indicated by an elevated concentration of blood-TG post-operatively if it was high pre-operatively. Post-operatively, TTH levels soared up in thyroid cancer and adenoma patients, reached their peak one month after surgery and then came back to normal while blood-TG concentration dropped to normal within 6-12 months. Unlike TA patients, blood-TG showed a continuous rise in those with TC. Ten years after surgery, blood-TTH levels in TC patients, who had received substitution hormone therapy, were much lower than in those without it. Similarly, the recipients of hormone therapy showed relatively lower T3 (6 months after operation) and TG (5 years after surgery) levels. Blood-TTH in overweight (Broca index > 20%) patients with TC was much higher than in those overweight less than 20%, 2 years after surgery. Elevated concentrations of blood-TTH and T3 were recorded in radically-treated patients with TC recurrences and metastases.
The following problems are discussed in this short review: (1) General issues (drugs, dosage, indications); (2) Risk of cancer development in women receiving estrogen-replacement therapy (ERT); (3) Attempts to extend ERT to breast and endometrial carcinoma patients; (4) Difficulties involved, doubts and perspectives.
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One hundred and eighteen primary breast cancer (BC) patients, 35 of whom were smokers, in clinical stages I-II of the disease were examined. In order to investigate whether smoking changes endocrine function in BC patients, some indices of the hormone-metabolic status of smoking and non-smoking patients of reproductive and menopausal age were compared. It was found that in smokers with BC there was a decline in body weight and body fat content, a lack of lean body mass accumulation along with body mass increase, a tendency to hypotriglyceridemia and hypoinsulinemia, accelerated development of the upper type of body fat distribution with ageing, intensified gonadotropin secretion, shifts in steroidogenesis and SHBG level and elevated catecholamine execretion. It is suggested that a possible relation between hormone-mediated effects inherent to smoking and the mechanisms promoting genotoxic type of hormonal carcinogenesis and the factors of breast cancer prognosis cannot be excluded.
Blood insulin level was measured in 113 breast cancer (BC) patients, 18 endometrial cancer (EC) patients, and 35 women with benign breast disease (BBD), after fasting and after 120 min of oral glucose tolerance test (OGTT). A significant increase in reactive insulin level was shown in postmenopausal BC patients with abdominal obesity (waist/hip ratio > 0.85) and no differences in insulin level were found between BC and BBD patients. Menstrual status and overweight (Quetelet index) did not influence significantly blood insulin concentration in BC patients, but the basal insulin level was lower in those patients who had been moderate smokers. In EC patients, the level of insulin after fasting and following 120 min OGTT was much higher than in BC and BBD patients although they had a similar body mass to these groups of patients. The effect of age on insulin secretion in BC patients is discussed as well as the possible causes and consequences of hyperinsulinemia developing in EC and BC patients.
Tumor sensitivity to gastrin in vitro (52) and blood gastrin (112) were assayed in cases of colorectal cancer before surgery. Hypergastrinemia was detected in almost half the group of patients with large bowel tumors. It was found to aggravate the short-term and end results of treatment. At least half the tumors retained sensitivity to gastrin, with prognosis being favorable. It is suggested that medication be used for hormono-metabolic correction and measures be taken to suppress gastrin secretion.
Over the past years, data on the role of DNA damage in hormonal carcinogenesis have been accumulated. In 21 endometrial cancer (EC) patients (mean age 61.8 +/- 1.6 years), no difference between malignant and normal endometrium in estradiol content (radioimmunological assay) and in alkali-induced DNA unwinding as a measure of DNA strand breakage (fluorometrical assay) was discovered. At the same time (contrary to normal endometrium), there were no correlations between the estradiol content in malignant endometrium with DNA unwinding or blood estrogen level. The estradiol concentration in malignant endometrium increases with age in menopausal EC patients, though no correlation between estrogen content in endometrial tissue and body weight was discovered. DNA unwinding rate in malignant endometrium correlates only with the concentration of steroid receptors in normal endometrial tissue. It may be possible that before the appearing of any neoplastic changes in the endometrium, a higher level of estradiol in the target tissue leads to DNA damage which may be considered as a factor predisposing to tumor development. Practically speaking this would mean that the estradiol content and DNA unwinding level in endometrial tumors may be used in future as indicators for therapeutic intervention (first of all, during the hormone therapy of EC) and also as markers for the evaluation of the effectiveness of the latter.
The precise place of local estrogen production in mammary cancer is still controversial. In this investigation localization of aromatase (the key enzyme of estrogen biosynthesis) was studied in breast cancer tissue by immunohistochemical method using polyclonal rabbit antibodies. The cytoplasmic staining was found in different cell types, but the most intensive specific staining was found in malignant cells and it was stronger (P < 0.01) in postmenopausal patients than in patients of reproductive age.
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Although a two-component model system (i.e. epithelial and stromal spindle-shaped cells) may explain the regulation of aromatase activity and the location of possible intratumoural sources of oestrogen production in mammary neoplasms, a third component, consisting of lymphocytes and macrophages, may also be considered. Examples are presented, suggesting the importance of a three-component model for a more complete understanding of the regulation of oestrogen production in breast-tumour tissue.
The purpose of this study was to investigate the peculiarities of hormonal regulation of adenylate cyclase (AC) of blood lymphocytes in colorectal cancer patients and to compare these peculiarities with hormone sensitivity of AC of colorectal tumors and normal colonic mucosa. Basal and stimulated lymphocyte AC activity was studied in 51 healthy persons and 52 cancer patients (14 with colon cancer, 21 with rectal cancer and 17 with stomach cancer) aged 20-75 years. In 31 of 35 patients with colorectal cancer the AC activity was studied simultaneously in lymphocytes, tumor tissue and normal colonic mucosa. To evaluate basal and stimulated AC activity the measurement of c-AMP (Amersham kits) formed in the presence of ATP regenerating system was used. Basal and by VIP, pentagastrin and sodium fluoride stimulated AC activity in lymphocytes of gastrointestinal cancer patients was lower than in lymphocytes of healthy subjects of similar age. Stage dependence of the parameters under study was not found. There was a tendency for higher basal and stimulated lymphocyte AC activity in colon cancer patients as compared to stomach and rectal cancer patients. In colorectal cancer patients the peculiarities of lymphocyte AC reactions to stimulation were closer to those in tumor tissue but not to those in normal colonic mucosa. The reaction of lymphocyte AC to VIP and glucagon coincided more frequently with tumor AC reactions to the same hormones in case of hormone nonsensitive tumors. Thus, basal and stimulated lymphocyte AC activity in colorectal cancer patients was modified to some degree by tumor factors. Lymphocyte AC reactions to VIP and glucagon may be considered as indirect markers of hormone sensitivity of colonic tumors. Moreover, the probability of discovery of hormone nonsensitive tumors by this way is more reliable than hormone sensitive ones.
A variety of data suggesting a relationship between estrogens and the immune system prompted a study of aromatase activity in blood lymphocytes. A tritiated water aromatase assay detected activity of 1.9 to 25.1 pmol/g protein/h in 14 samples of human lymphocytes. To confirm these results, additional tritiated water and product isolation assays were performed on a large pool of lymphocytes obtained from 4 U of blood. An assay using [1 beta-3H]androstenedione generated high apparent aromatase activity, 943 pmol/g protein/h, but this activity could not be blocked by the aromatase inhibitor, CGS 16949A. More direct methods of evaluation yielded the following results: (1) PCR demonstrated no aromatase mRNA production in lymphocytes; (2) direct product isolation using [1,2,6,7-3H]androstenedione yielded insignificant production of estrone and estradiol; (3) immunostaining of fixed lymphocyte smears with a polyclonal antibody to aromatase yielded equivocal results. These data suggest the presence of pseudoaromatase in blood lymphocytes. Since circulating lymphocyte pseudoaromatase levels can be correlated with various factors in patients, such as age, menopausal status, and glucose ingestion, further studies of this activity are warranted.
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