Use of vitamin E in chronic cystic mastitis.

Abrams, A.

N. Engl. J. Med. 1965; 272: 2388.

No Abstract Available

The effect of decreased caffeine consumption on benign proliferative breast disease: a randomized clinical trial.

Allen, S.S., Froberg, D.C.

Surgery 1985; 91: 263.

No abstract available.

The effect of decreased caffeine consumption on benign proliferative breast disease: a randomized clinical trial.

Allen SS, Froberg DG.

Surgery 1987 Jun;101(6):720-30

A single-blind, randomized clinical trial of 56 female subjects was conducted to determine whether decreased consumption of caffeine decreases breast pain/tenderness or nodularity in patients with suspected benign proliferative breast disease. The subjects were randomly assigned to one of three groups--a control group (no dietary restrictions), a placebo group (cholesterol-free diet), and an experimental group (caffeine-free diet). At the initial examination, the subjects reported on the presence of breast pain, the degree to which pain affects daily activities, the frequency of pain, the degree of pain associated with breast examinations, and the degree of pain associated with close-fitting clothing. Subjects were then examined and the four quadrants of each breast were rated on a scale of 0 to 3 (0 = normal, fatty tissue, 1 = little seedy bumps or fine nodularity, 2 = discrete nodules or ropy tissue, 3 = confluent areas, hard or soft masses). Subjects in all three groups returned for 2- and 4-month follow-up examinations. Total nodularity scores, degree of pain/tenderness, and compliance with dietary restrictions were analyzed. The data showed that decreased caffeine consumption did not result in a significant reduction of palpable breast nodules or in a lessening of breast pain/tenderness.

Benign Breast Conditions 1991, 1997.

Atlanta, GA: American Cancer Society.

American Cancer Society.

Caffeine labeling, a report on the safety of dietary caffeine.

AMA. American Medical Association's Council on Scientific Affairs.

JAMA 1984; 252: 803-6.

The American Medical Association Encyclopedia of Medicine 1989.

AMA.

New York: Random House.

Dietary fiber content of selected foods.

Anderson JW, Bridges SR. VA Medical Center, Lexington, KY 40511.

Am J Clin Nutr 1988 Mar;47(3):440-7

Dietary fiber measurements are essential to assessment of the potential therapeutic and preventive effects of fiber intake. Ideally, dietary fiber analyses should measure all components--soluble polysaccharides, noncellulosic polysaccharides, cellulose, and lignin--and the constituent sugars of the soluble and noncellulosic polysaccharides. We modified existing techniques to measure reproducibly the total dietary fiber, polysaccharide, and lignin components and the sugar constituents of selected foods. Soluble-fiber content as percentage of total dietary fiber for groups of foods averaged 32% for cereal products, 32% for vegetables, 25% for dried beans, and 38% for fruits. Lignin content, estimated gravimetrically, was approximately 1.4 g/100 g dry wt for 24 foods. Detailed fiber measurements are critical for evaluating the potential health benefits of dietary fiber intake.

Benign breast conditions.

Anon.

Reinsurance Notes 1998; 1: 12.

Professional Guide to Signs & Symptoms, Third Edition 2000.

Anon.

Springhouse, PA: Springhouse.

Indole-3-carbinol as a scavenger of free radicals.

Arnao MB, Sanchez-Bravo J, Acosta M. Department of Plant Biology (Plant Physiology), University of Murcia, Spain.

Biochem Mol Biol Int 1996 Aug;39(6):1125-34

The ability of indole-3-carbinol (indole-3-methanol) to trap a metastable synthetic-free radical is presented. Indole-3-carbinol is capable of acting as a scavenger of free radicals in an in vitro system. The presence of indole-3-carbinol determines the disappearance of the free radicals, the reaction being time- and concentration-dependent. The scavenging activity of different indoles is compared. Indole-3-carbinol and indole-3-acetic acid are both able to scavenge free radicals, but indole-3-carbinol is more effective. Other indoles such as indole-3-aldehyde and indole-3-carboxylic acid do not show the ability to trap free radicals. Indole-3-aldehyde appears as a product of indole-3-carbinol reaction with free radicals. The formation of an adduct between the free radical generated in vitro and indole-3-carbinol has also been detected. Stability of indole-3-carbinol in buffered media at different pH values and formation of 3,3'-diindolylmethane from indole-3-carbinol is also studied. The scavenging activity of indole-3-carbinol and its implications on the anti-carcinogenesis process is discussed.

Dietary glycemic index and glycemic load, and breast cancer risk: a case-control study.

Augustin LS, Dal Maso L, La Vecchia C, Parpinel M, Negri E, Vaccarella S, Kendall CW, Jenkins DJ, Francesch S. Servizio di Epidemiologia, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, Italy.

Ann Oncol 2001 Nov;12(11):1533-8

BACKGROUND: Certain types of carbohydrates increase glucose and insulin levels to a greater extent than others. In turn, insulin may raise levels of insulin-like growth factors, which may influence breast cancer risk. We analyzed the effect of type and amount of carbohydrates on breast cancer risk, using the glycemic index and the glycemic load measures in a large case-control study conducted in Italy. PATIENTS AND METHODS: Cases were 2,569 women with incident, histologically-confirmed breast cancer interviewed between 1991 and 1994. Controls were 2588 women admitted to the same hospital network for a variety of acute, non-neoplastic conditions. Average daily glycemic index and glycemic load were calculated from a validated 78-item food frequency questionnaire. RESULTS: Direct associations with breast cancer risk emerged for glycemic index (odds ratio, OR for highest vs. lowest quintile = 1.4; P for trend < 0.01) and glycemic load (OR = 1.3; < 0.01). High glycemic index foods, such as white bread, increased the risk of breast cancer (OR = 1.3) while the intake of pasta, a medium glycemic index food, seemed to have no influence (OR = 1.0). Findings were consistent across different strata of menopausal status, alcohol intake, and physical activity level. CONCLUSIONS: This study supports the hypothesis of moderate, direct associations between glycemic index or glycemic load and breast cancer risk and, consequently, a possible role of hyperinsulinemia/insulin resistance in breast cancer development.

The "luteal breast": hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.

Ayers JW, Gidwani GP.

Fertil Steril 1983 Dec;40(6):779-84

The pathophysiology, malignant potential, and hormonal therapy for benign breast disease remain controversial. This report investigates the anatomic and endocrinologic correlates of luteal phase mastodynia patients, compared with asymptomatic control subjects. Objective sonographic evidence of fibrocystic disease (FCD) was found in one-half of both mastodynia and control groups. Endocrine abnormalities observed in the mastodynia group included (1) significantly lower luteal phase progesterone and (2) prolactin hyperresponsiveness to thyroid-releasing factor. The presence or absence of anatomic FCD was not correlated with endocrine abnormalities. These data suggest that (1) cyclic mastalgia may be the end result of a dyshormonal milieu resembling the inadequate luteal phase; (2) FCD may be hormonally independent; and (3) cyclic mastalgia and FCD are different, if often coexistent, factors in benign breast disease syndromes.

Treatment of benign breast disease with vitamin A.

Band PR, Deschamps M, Falardeau M, Ladouceur J, Cote J.

Prev Med 1984 Sep;13(5):549-54

Twelve patients with benign breast disease (BBD) were treated with 150,000 IU of vitamin A daily taken orally. All patients were symptomatic and had measurable or evaluable breast masses. At 3 months of treatment, complete or partial responses were observed in five patients, and marked pain reduction in nine was observed. Side effects were generally mild in nature, consisting mostly of skin and mucosal changes, and were rapidly reversible upon discontinuation of the drug. Treatment was interrupted or discontinued in only two patients, and the dosage of vitamin A was reduced in one on account of toxicity. No hepatotoxicity was observed. Investigation of the chemopreventive role of either vitamin A or retinoids in patients with BBD who are at high risk of developing breast cancer is suggested.

Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid.

Banni S, Angioni E, Casu V, Melis MP, Carta G, Corongiu FP, Thompson H, Ip C. Dipartimento di Biologia Sperimentale, Sezione di Patologia Sperimentale, Universita degli Studi di Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy.

Carcinogenesis 1999 Jun;20(6):1019-24

Previous research suggested that conjugated linoleic acid (CLA) feeding during the period of pubescent mammary gland development in the rat resulted in diminished mammary epithelial branching which might account for the reduction in mammary cancer risk. Terminal end buds (TEB) are the primary sites for the chemical induction of mammary carcinomas in rodents. One of the objectives of the present study was to investigate the modulation of TEB density by increasing levels of dietary CLA and to determine how this might affect the risk of methylnitrosourea-induced mammary carcinogenesis. The data show a graded and parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1% CLA. No further decrease in either parameter was observed when CLA in the diet was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the mammary gland. Since both CLA and linoleic acid are likely to share the same enzyme system for chain desaturation and elongation, it is possible that increased CLA intake may interfere with the further metabolism of linoleic acid. Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2% CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to 1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose-response effect on cancer protection in the mammary gland. This information is critical in providing new insights regarding the biochemical action of CLA.

The epidemiology of DHEAS and cardiovascular disease.

Barrett-Connor E, Goodman-Gruen D. Department of Family and Preventive Medicine, University of California, San Diego, La Jolla 92093-0607, USA.

Ann N Y Acad Sci 1995 Dec 29;774:259-70

In 1986 we reported that high levels of plasma dehydroepiandrosterone sulfate (DHEAS) reduced the risk of fatal cardiovascular disease (CVD) in 242 men and increased the risk in 289 women from the Rancho Bernardo cohort who were followed up for 12 years. We report here an update on the epidemiology of DHEAS and CVD based on a 19-year follow-up of 1,029 men and 942 women aged 30-88 years from the same cohort. In cross-sectional analyses, DHEAS levels decreased with age in both sexes and were lower in women than men. Men who were overweight were more likely to have low DHEAS levels; women who had hypercholesterolemia or hypertension or were nonusers of estrogen therapy had higher DHEAS levels. Alcohol intake and cigarette smoking were associated with higher DHEAS levels in both sexes. All differences were no longer statistically significant after adjusting for alcohol intake. All participants were followed for vital status. After 19 years there were 254 CVD deaths in men and 199 CVD deaths in women. DHEAS was not associated with CVD or ischemic heart disease (IHD) deaths in age-adjusted analyses where the comparison group was individuals without CVD or IHD death. In contrast, when the comparison group was survivors, multiply adjusted models showed a statistically significant, modestly reduced risk of fatal CVD (RR = 0.85) in men and a nonsignificant increased risk of fatal CVD (RR = 1.11) in women.

Breast sonography.

Bassett, L.W., Kimme-Smith, C.

Am. J. Roentgenol. 1991; 156: 449-55.

No abstract available.

Effects of obesity on sex steroid metabolism.

Bates GW, Whitworth NS.

J Chronic Dis 1982;35(12):893-6

In a study designed to compare plasma androgens in obese, anovulatory women with non-obese, ovulatory women, we found a statistically significant increase in plasma androstenedione and testosterone in obese, anovulatory women. Plasma androstenedione was 252 18 ng/dl (mean SEM) in the obese women compared with 173 9 ng/dl in the non-obese ovulatory women (p less than 0.001). Plasma testosterone was 66 5.7 ng/dl (mean SEM) in the obese women compared with 41 3.0 ng/dl in the non-obese ovulatory women (p less than 0.001). Androstenedione and testosterone are the substrates for estrone and estradiol-17 beta production. Menstrual disorders associated with obesity are largely due to estrogen excess. From the findings of this study we suggest that androgen excess in obesity results in subsequent tonic estrogen production and estrogen excess.

Fruits and Vegetables and the Risk of Breast Cancer 1998 Dec.

BCERF. Program on Breast Cancer and Environmental Risk Factors in New York State. Ithaca, NY: Cornell University.

No abstract available.

Evening primrose oil and borage oil in rheumatologic conditions.

Belch, J.J., Hill, A. Department of Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom. j.j.f.belch@dundee.ac.uk

Am. J. Clin. Nutr. 2000 Jan; 71(1, Suppl.): 352S-356S.

Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects. Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase (prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of LTB(4), a potent inflammatory mediator) to continue. Altering the essential fatty acid (EFA) content of the diet can modify some of these effects. Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo-gamma-linolenic acid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE(1). DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation. The results of in vitro and animal work evaluating EFAs in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis. Several well-controlled, randomized clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these treatments; these data are reviewed here.

Mastodynia.

BeLieu RM. Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine.

Obstet Gynecol Clin North Am. 1994 Sep;21(3):461-77.

The most important factors in the evaluation and treatment of breast pain consist of a thorough history, physical, and radiologic evaluation. These can be used to reassure the patient that she does not have breast cancer. In the 15% of mastalgia patients who have life-altering pain and still request treatment, therapy may consist of a well-fitting bra, a decrease in dietary fat intake, and discontinuance of oral contraceptives or hormone replacement therapy. Those women still resistant to therapy may experience relief from evening primrose oil supplements, bromocriptine, tamoxifen, or GnRH analogues. Predicting which treatment will be most useful for any particular woman may be challenging. No differences in success rates were found to be associated with factors such as reproductive history, presenting complaint, personal or family history of breast disease, or subsequent need for breast surgery. The peak (but not basal) serum prolactin levels in response to thyrotropin releasing hormone stimulus has been predictive of success for hormonal treatment but is relatively invasive. A survey of treatments actually used was obtained from 276 consultant surgeons in Britain in 1990. Of those, 75% prescribed danazol. Others used analgesia (21%), diuretics (18%), local excision (18%), bromocriptine (15%), evening primrose oil (13%), tamoxifen (9%), a well-fitting bra (3%), and no treatment (10%). Breast specialists were more likely to begin treatment with primrose oil, tamoxifen, vitamin B6, and analgesia, reserving other hormonal therapies for more difficult cases. To further evaluate the women who have severe mastalgia but do not complete treatment regimens, a questionnaire was sent to 79 patients who failed to return to the Longmore Breast Unit of Western General Hospital, Edinburgh. Seventy-one women responded. Of these, 36 said they felt better, 19 said they felt no more could be done, 18 learned to live with it, 14 were not worried even if the pain recurred, 2 were pregnant, 10 were postmenopausal, and 5 were still taking the medications previously prescribed. The prognosis for women with breast pain is not always predictable. Women with cyclic breast pain often are relieved by events that alter their hormonal milieu, whereas noncyclic breast pain may last only 1 to 2 years. Sitruk-Ware and colleagues conducted a study of French women with fibroadenomas. They found an association between fibroadenomas and cyclic mastalgia occurring more than 1 year prior to the first full-term pregnancy. A retrospective, case-control study to determine if cyclic mastalgia was a risk factor for breast cancer was conducted on 210 newly diagnosed women with breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Severe sexual impairment produced by morbid obesity. Report of a case.

Blum I, Marilus R, Barasch E, Sztern M, Bruhis S, Kaufman H. Department of Medicine C, Rokach (Hadassah) Hospital, Tel-Aviv, Israel.

Int J Obes 1988;12(3):185-9

A 45-year-old man, was admitted for investigation of severe sexual impairment. During 20 years of marriage, he had had no normal sexual intercourse and the couple was childless. Physical examination disclosed a severely obese man (weight 300 kg, height 1.75 m), with a relatively small and invaginated penis and small (5 ml) soft testes. Laboratory examinations disclosed the following: low serum testosterone (1 ng/ml), with a reduced response to HCG (3.8 ng/ml). Sex hormone binding globulin was at the lower limit of normal (0.38 microgram/dl), serum free testosterone was low (0.98% of total testosterone) as well as non-SHBG bound testosterone (22% of total testosterone). Daily total urinary estrogen excretion was increased (107 micrograms), the plasma estrone (78 pg/ml) and estradiol (74 pg/ml) were elevated. The gonadotropins were normal and responded adequately to LRH. Plasma growth hormone was decreased, prolactin, T4 and adrenal steroids were normal and responded normally to stimuli and inhibitors. Chromosomal constitution was 46XY. Thus, in this man the marked obesity produced a significant increase in estrogens which subsequently induced a severe decrease in testosterone and its free counterpart in excessive impairment of sexual function.

Benign breast diseases, carcinoma in situ, and breast cancer risk.

Bodian, C.A.

Epidemiol. Rev. 1993a; 15: 177-87.

No abstract available.

Prognostic significance of benign proliferative breast disease.

Bodian CA, Perzin KH, Lattes R, Hoffmann P, Abernathy TG.Department of Biomethematical Sciences, Mount Sinai Medical Center, New York, New York 10029.

Cancer 1993b Jun 15; 71(12): 3896-3907.

BACKGROUND. Recent studies concerning an association between benign breast diseases and risk of subsequent breast cancer have focused on benign proliferative lesions recognized in biopsy specimens. Some have implicated atypical hyperplasia as being associated with the greatest risk. METHODS. The histologic sections of specified benign breast lesions from 1799 women were reviewed and reclassified, using published criteria for proliferative disease. Prognostic significance was assessed by relating the pathologic findings to the development of breast cancer observed during an average 21 years of follow-up, in which time 157 women developed the disease. RESULTS. Benign proliferative changes were recognized in 85% of the patients, with a corresponding relative risk of subsequent carcinoma equal to 2.2 times population rates (95% confidence limits, 1.9 and 2.6). Increasing levels of hyperplasia and atypia in lobules or ducts were associated with modest increases in risk, ranging from 2.1 to 2.3 to 3.0 for proliferative changes with no atypia, mild atypia, and moderate to severe atypia, respectively. This trend was not statistically significant. The most significant risk indicators in this study were the presence of adenosis (relative risk, 3.7), and moderate or severe atypia in ducts (relative risk, 3.9). CONCLUSIONS. Benign proliferative breast disease recognized in biopsy specimens is associated with an increased risk of future breast cancer, but fine distinctions among levels of hyperplasia and atypia did not significantly distinguish risk among patients in this study.

Reproducibility and validity of pathologic classifications of benign breast disease and implications for clinical applications.

Bodian CA, Perzin KH, Lattes R, Hoffmann P. Department of Biomathematical Sciences, Mount Sinai Medical Center, New York, NY 10029.

Cancer 1993c Jun 15; 71(12): 3908-13.

BACKGROUND. Research studies on the relationship between benign breast diseases and cancer risk typically identify certain conditions as risk factors, and others as carrying no prognostic significance. This study addresses several issues concerning the relevance of such research results for advising individual patients in a clinical setting. METHODS. Data were obtained as part of a "blinded" retrospective pathology review of benign breast biopsies. A random sample of cases was reviewed twice, providing information about reliability. Comparisons with diagnoses that used information from the operative reports and gross pathology descriptions as well as microscopic histology were used to assess validity. RESULTS. Among cases that were reviewed twice, excellent agreement was achieved for diagnosing carcinoma and lobular neoplasia, good agreement for adenosis and intraductal papilloma, and relatively poor agreement about levels of hyperplasia and atypia, and whether ducts or lobules were involved. Distinctions among levels of hyperplasia also apparently were influenced by the number of slides available for review. The "blinded" review diagnoses frequently differed from the diagnoses that used all information available at the time of surgery in detecting the presence or absence of gross cystic disease, and in distinguishing solitary from multiple papillomas. CONCLUSIONS. Problems with reliability of precise distinctions among levels and sites of hyperplasia and atypia seem to limit the usefulness of such classifications as guidelines for individual patient care. For conditions with some clinical manifestations, diagnoses based exclusively on histologic review of biopsy specimens often are not accurate.

Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.

Boyd NF, McGuire V, Shannon P, Cousins M, Kriukov V, Mahoney L, Fish E, Lickley L, Lockwood G, Tritchler D. Ludwig Institute for Cancer Research, Toronto Branch, Ontario, Canada.

Lancet 1988 Jul 16;2(8603):128-32

21 patients with severe persistent cyclical mastopathy of at least 5 years' duration were randomised to a control group who received general dietary advice or to an intervention group who were taught how to reduce the fat content of their diet to 15% of calories while increasing complex carbohydrate consumption to maintain caloric intake. Both groups were followed for 6 months with food records and measurement of plasma hormone and lipid levels. Severity of symptoms was recorded with daily diaries and patients were assessed at the beginning and end of the study by a physician who was unaware of their dietary regimen. After 6 months there was a significant reduction in the intervention group in the severity of premenstrual breast tenderness and swelling. Physical examination showed reduced breast swelling, tenderness, and nodularity in 6 of 10 patients in the intervention group and 2 of 9 patients in the control group.

Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group.

Boyd NF, Greenberg C, Lockwood G, Little L, Martin L, Byng J, Yaffe M, Tritchler D. Division of Epidemiology and Statistics, Ontario Cancer Institute, Toronto, Canada.

J Natl Cancer Inst 1997 Apr 2;89(7):488-96

BACKGROUND: The appearance of breast tissue on mammography varies according to its composition. Fat is radiolucent and appears dark on mammography, while stromal and epithelial tissue has greater optical density and appears light. Extensive areas of radiologically dense breast tissue seen on mammography are associated with an increased risk of breast cancer. PURPOSE: The purpose of the present study was to determine whether the adoption of a low-fat, high-carbohydrate diet for 2 years would reduce breast density. METHODS: Women with radiologic densities in more than 50% of the breast area on mammography were recruited and randomly allocated to an intervention group taught to reduce intake of dietary fat (mean, 21% of calories) and increase complex carbohydrate (mean, 61% of calories) or to a control group (mean, 32% of calories from fat and 50% of calories from carbohydrates). Mammographic images from 817 subjects were taken at baseline and compared with those taken 2 years after random allocation by use of a quantitative image analysis system, without knowledge of the dietary group of the subjects or of the sequence in which pairs of images had been taken. The effects of the intervention on the mammographic features of breast area, area of dense tissues in the breast, and the percent of the breast occupied by dense tissue were examined using t tests. Multiple regression was used to examine these effects while accounting for age at trial entry, weight change, and menopausal status. RESULTS: After 2 years, the total area of the breast was reduced by an average of 233.7 mm2 (2.4%) (95% confidence interval [CI] = 106.9-360.6) in the intervention group compared with an average increase of 26.3 mm2 (0.3%) (95% CI = -108.0-160.5) in the control group (P = .01). The area of density was reduced by 374.4 mm2 (6.1%) (95% CI = 235.1-513.8) in the intervention group compared with an average of 127.7 mm2 (2.1%) (95% CI = 8.6-246.7) in the control group (P = .01). Weight loss was associated with a reduction in breast area. The effect of the intervention on breast area was only marginally statistically significant after weight change, menopausal status, and age at trial entry were taken into account (P = .06). Greater weight loss and becoming postmenopausal were associated with statistically significant reductions in the area of density on the mammographic image at 2 years (P = .04 and < 001, respectively). Age at entry into the trial was marginally significant in the same direction (P = .06). The effect of the intervention on area of density remained statistically significant after controlling for weight loss, age at entry, and menopausal status (P = .03). The change in the percentage of dense tissue in the mammographic image was not significantly different between the two groups (P = .71). CONCLUSIONS AND IMPLICATIONS: These results show that after 2 years, a low-fat, high-carbohydrate diet reduced the area of mammographic density, a radiographic feature of the breast that is a risk factor for breast cancer. Longer observation of a larger number of subjects will be required to determine whether these effects are associated with changes in risk of breast cancer.

Caffeine consumption and fibrocystic breast disease: a case-control epidemiologic study.

Boyle CA, Berkowitz GS, LiVolsi VA, Ort S, Merino MJ, White C, Kelsey JL.

J Natl Cancer Inst 1984 May;72(5):1015-9

In a hospital-based case-control study that included 634 women with fibrocystic breast disease and 1,066 comparison women in Connecticut, the occurrence of fibrocystic breast disease was positively associated with average daily consumption of caffeine. Women who consumed 31-250 mg of caffeine/day had a 1.5-fold increase in the odds of disease, whereas womitant papillomatosis or papillary hyperplasia, both of which have been associated with an increased breast cancer risk. The association was specific to fibrocystic breast disease in that there was no association of cafen who drank over 500 mg/day had a 2.3-fold increase in the odds. The association with caffeine consumption was especially high among women with atypical lobular hyperplasia and with sclerosing adenosis with concomfeine consumption with fibroadenoma or other forms of benign breast disease.

Long-term responses of women to indole-3-carbinol or a high fiber diet.

Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Institute for Hormone Research, New York, New York 10021-4004.

Cancer Epidemiol Biomarkers Prev 1994 Oct-Nov;3(7):591-5

We test the hypothesis that the estrogen metabolite ratio 2-OH-estrone:estriol can be raised via dietary indole-3-carbinol (I3C) and that this higher ratio can be sustained over a 3-month test period. We also explore the possible role of pure fiber on estradiol metabolism. Using a randomized clinical trial with three arms, each containing 20 subjects, arm 1 received 400 mg/day of I3C daily for 3 months, arm 2 received 20 g of alpha-cellulose daily for the same time period as a source of added fiber, and arm 3 received a placebo dose. Blood levels of a variety of biochemical parameters were measured. The urinary 2-OH-estrone:estriol estrogen metabolite ratio was measured monthly at the same time of the menstrual cycle. While no changes were observed in the control and alpha-cellulose-treated arms, a substantial mean increase in the ratio was observed in the I3C-treated arm at month 1; that increase was maintained over the 3-month time period. Three of the 20 subjects in this I3C-treated group differed from the others in that no significant change in the metabolite ratio was observed at any time point. The results suggest that I3C can serve to increase the 2-OH-estrone:estriol metabolite ratio in a sustained manner without detectable side effects and that some individuals may be resistant to such change.

Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent.

Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Strang Cancer Research Laboratory, New York, New York 10021, USA. leon@rockvax.rockefeller.edu

Ann N Y Acad Sci 1999;889:204-13

Previous studies from this laboratory have suggested that 2-hydroxyestrone is protective against breast cancer, whereas the other principal metabolite, 16 alpha-hydroxyestrone, and the lesser metabolite quantitatively, 4-hydroxyestrone, are potent carcinogens. Attempts to directly decrease the formation of the 16-hydroxylated metabolite were either unsuccessful or required such high levels of the therapeutic agent as to be impractical. On the other hand the concentration of the protective metabolite, 2-hydroxyestrone, proved to be readily modulated by a variety of agents, both in the direction of increased protection and the opposite direction, increased risk by a variety of agents and activities. We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1. In addition to these indirect effects as a result of altered estrogen metabolism, indole-3-carbinol has been shown to have direct effects on apoptosis and cyclin D, resulting in blockage of the cell cycle. In addition to its antitumor activity in animals, it has also been shown to be effective against HPV-mediated tumors in human patients. All of these responses make the study of its behavior as a therapeutic agent of considerable interest.

Phytochemicals as modulators of cancer risk.

Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. Strang Cancer Research Laboratory, New York, NY 10021, USA.

Adv Exp Med Biol 1999;472:207-21

These results, describing antitumor activity of some of the phytochemicals that have been actively studied, suggest that dietary changes could play a role in decreasing the incidence of a variety of tumors. 13C and the other compounds discussed may well be only prototypes for other as yet unexplored phytochemicals present in the diet. There have been no attempts to explore the possibilities of synergistic action among the various phytochemicals, 13C, limonene, curcumin, epigallocatechin gallate, sulforaphene, or genistein. Mixtures of these compounds might well show potency at lower doses for each of the compounds and show even greater promise than that already demonstrated.

Is there an increased risk of breast cancer in women who have had a breast cyst aspirated?

Bundred NJ, West RR, Dowd JO, Mansel RE, Hughes LE. Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff, UK.

Br J Cancer. 1991 Nov;64(5):953-5.

A consecutive series of 644 women who presented with breast nodularity between 1976 and 1982 have been followed up to determine their rate of subsequent breast cancer. Fifteen women have developed breast cancer, 14 of these were among 352 women with an aspirated cyst (relative risk 4.4). Women with multiple cysts had the highest risk and women with breast nodularity had no excess risk. Review of histology specimens from those women who had undergone biopsy showed an excess of florid epithelial hyperplasia in women who subsequently developed breast cancer and women with multiple aspirated cysts were more likely to have florid epithelial hyperplasia. Multiple cysts are clinical markers of histological breast proliferation and women who have had multiple breast cysts aspirated have an increased risk of breast cancer and should be advised to practice regular self examination.

Identifying the Breast Cancer Target for Indole-3-Carbinol (unpublished).

Chatterji, U.

Postdoctorate Fellowship 2001-2002. Berkeley, CA: University of California.

Management of cyclical mastalgia in oriental women: pioneer experience of using gamolenic acid (Efamast) in Asia.

Cheung KL. Department of Surgery, The University of Hong Kong, Queen Mary Hospital and Tung Wah Hospital. mszklc@msnl.surgery.nottingham.ac.uk

Aust N Z J Surg. 1999 Jul;69(7):492-4.

BACKGROUND: In most Western countries gamolenic acid is the first-line treatment for women with cyclical mastalgia. METHODS: A prospective study was carried out in the breast referral clinic of the Department of Surgery, University of Hong Kong to evaluate the treatment of cyclical mastalgia using gamolenic acid provided in evening primrose oil (Efamast, Scotia Pharmaceuticals Ltd, Scotia House, Stirling, Scotland) as a pioneer experience in Asia. In addition, the features of cyclical mastalgia in Oriental women were studied by conducting a survey using anonymous questionnaires. RESULTS: Sixty-six women with disturbing cyclical mastalgia seen by one breast surgeon were followed up with a breast pain diary. Thirty-four women had persistently disturbing mastalgia and were commenced on Efamast. Responses were measured at 3 and 6 months according to a standardized protocol. An overall useful response rate of 97% was observed at 6 months. Side-effects were found in 12% but all were insignificant. CONCLUSIONS: Efamast may be recommended as a first-line specific treatment for Oriental women with disturbing cyclical mastalgia.

Alternation of hepatic antioxidant enzyme activities and lipid profile in streptozotocin-induced diabetic rats by supplementation of dandelion water extract.

Cho SY, Park JY, Park EM, Choi MS, Lee MK, Jeon SM, Jang MK, Kim MJ, Park YB. Department of Food and Nutrition, Yeungnam University, Kyongsan 712-749, South Korea.

Clin Chim Acta. 2002 Mar;317(1-2):109-17.

BACKGROUND: Dandelion water extract (DWE), an herbal medication, may have an effect on the activity and mRNA expression of hepatic antioxidant enzymes and lipid profile in streptozotocin (STZ)-induced diabetic rats. METHODS: Male Sprague-Dawley rats were divided into nondiabetic (control), diabetic, and diabetic-DWE-supplemented groups. Diabetes was induced by injecting streptozotocin (55 mg/kg BW, i.p.) in a citrate buffer. The extract was supplemented in 2.4 g of a DWE/kg diet. RESULTS: The DWE supplement significantly decreased the serum glucose concentration in the diabetic rats. The hepatic superoxide dismutase and catalase activities significantly increased and the GSH-Px activity decreased in the diabetic rats, compared with the control group. When the DWE supplement was given to the diabetic rats, the antioxidant enzyme activity reverted to near-control values. However, there was no difference in the mRNA expression concentrations of these enzymes between the groups. With regard to the hepatic lipid peroxidation product, the malondialdehyde (MDA) content was significantly higher in the diabetic group than in the nondiabetic group. However, the DWE supplement lowered the hepatic MDA concentration in the diabetic-induced rats. The DWE supplement also lowered the total cholesterol and triglyceride concentrations in the serum and hepatic tissue, while increasing the serum HDL-cholesterol in the diabetic rats. CONCLUSIONS: A DWE supplement can improve the lipid metabolism and is beneficial in preventing diabetic complications from lipid peroxidation and free radicals in diabetic rats.

Nutrient intake, adiposity, plasma total cholesterol, and blood pressure of rural participants in the (Vermont) Nutrition Program for Older Americans (Title III).

Clarke RP, Schlenker ED, Merrow SB.

Am J Clin Nutr. 1981 Sep;34(9):1743-51.

The interrelationships of obesity, hypertension, elevated plasma cholesterol (risk factors), and intakes of selected nutrients were examined among elderly subjects attending a congregate meal program in Vermont. Mean nutrient intakes were significantly higher for 22 males compared to 69 females. Mean plasma cholesterol levels were higher in females. Age, systolic and diastolic blood pressure, and indices of adiposity showed no sex differences. Intakes of total fat and animal protein increased in males but plasma cholesterol decreased with age. Systolic blood pressure in females increased while body mass index decreased with age. A higher proportion of females had plasma cholesterol levels greater than or equal 260 mg/100 ml and a higher proportion of females than males greater than 73 yr of age had blood pressures at risk level. There was a greater proportion of females than males with both elevated plasma cholesterol levels and adiposity. Similarly the females had greater incidence of the combination of any two risks. No males, compared to 9% of females, were in the all three risk category.

In vivo dehydroepiandrosterone restores age-associated defects in the protein kinase C signal transduction pathway and related functional responses.

Corsini E, Lucchi L, Meroni M, Racchi M, Solerte B, Fioravanti M, Viviani B, Marinovich M, Govoni S, Galli CL. Department of Pharmacological Sciences, University of Milan, Milan, Italy. emanuela.corsini@unimi.it

J Immunol 2002 Feb 15;168(4):1753-8

Elderly subjects are at increased risk of pneumonia, influenza, and tuberculosis. Besides the known age-related decrease in mechanisms for mechanical clearance of the lungs, impaired alveolar macrophage function contributes to the increased risk of illness in the elderly. We have previously shown that age-induced macrophage immunodeficiencies are associated with a defective system for anchoring protein kinase C. Castration of young male rats produces effects on alveolar macrophages similar to those of aging, suggesting a relationship between circulating sex hormones, particularly androgens, and the decreases in the receptor for activated C kinase (RACK-1) and macrophage function observed. The aging process in humans and rats is associated with a decline in the plasma concentrations of dehydroepiandrosterone (DHEA) and its sulfate, among other steroid hormones. We report here that in vitro and in vivo administration of DHEA to rats restores the age-decreased level of RACK-1 and the LPS-stimulated production of TNF-alpha in alveolar macrophages. DHEA in vivo also restores age-decreased spleen mitogenic responses and the level of RACK-1 expression. These findings suggest that the age-related loss in immunological responses, linked to defective pathways of signal transduction, are partially under hormonal control and can be restored by appropriate replacement therapy.

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells.

Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF, Firestone GL. Department of Molecular and Cell Biology and The Cancer Research Laboratory, The University of California at Berkeley, 94720-3200, USA.

Cancer Res 1999 Mar 15;59(6):1244-51

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer.

[Risk factors associated with obesity: a metabolic perspective] [Article in French]

Despres JP, Pascot A, Lemieux I. Institut de cardiologie de Quebec, Centre de recherche de l'Hopital Laval, Pavillon Mallet, 2e etage, 2725, chemin Sainte-Foy, Sainte-Foy (Quebec), GIV 4G5. jean-pierre.depres@crchul.ulaval.ca

Ann Endocrinol (Paris) 2000 Dec;61 Suppl 6:31-38

Obesity, especially visceral obesity, is associated with a cluster of metabolic complications increasing the risk of type 2 diabetes and coronary heart disease. It has been shown that obese patients characterized by a high accumulation of visceral adipose tissue have increased glycemic and insulinemic responses to an oral glucose load compared to normal weight individuals or to obese individuals with a low accumulation of visceral adipose tissue. Viscerally obese patients are also characterized by an unfavourable plasma lipid profile which includes elevated triglyceride and apolipoprotein B concentrations, reduced HDL-cholesterol levels as well as an increased proportion of small, dense LDL particles. Such alterations in the lipid profile are often observed even in the absence of elevated LDL-cholesterol concentrations. Our work has clearly shown that this cluster of metabolic abnormalities found among viscerally obese patients was associated with a substantial increase in coronary heart disease risk. Our work has also shown that the "metabolic triad" of non-traditional risk factors (hyperinsulinemia, elevated apolipoprotein B levels, increased proportion of small, dense LDL particles) was associated with a 20-fold increase in the risk of coronary heart disease. In this regard, we have been interested in developing simple tools which would allow clinicians to identify at an early stage and at low cost individuals who would be carriers of the atherogenic metabolic triad. We have noted that the measurement and interpretation of waist circumference and of fasting plasma triglyceride levels could allow the identification of a high proportion of carriers of the metabolic triad. Indeed, less than 10% of men with a waist circumference below 90 cm and triglyceride concentrations below 2 mmol/l were characterized by the features of the metabolic triad. However, more than 80% of individuals with a waist circumference above 90 cm and triglyceride levels above 2 mmol/l were carriers of the metabolic triad. Finally, an elevated visceral adipose tissue accumulation has also been associated with a thrombogenic and a pro-inflammatory metabolic profile which would be predictive of an unstable atherosclerotic plaque. Therefore, the stabilisation of the atherosclerotic plaque may represent a legitimate therapeutic objective to reduce the risk of coronary heart disease among patients with visceral obesity. It is proposed that a rather modest weight loss (approximately 10%) could contribute to substantially improve the risk profile of these patients.

Treatment of fibrocystic mastopathy with hydrolytic enzymes

Ditmar F.-W.; Luh W. Dept. Obstetrics and Gynecology, District Hospital Starnberg, Osswaldstr 1,D-82319 Starnberg Germany

International Journal of Experimental and Clinical Chemotherapy (Germany) 1993, 6/1 (9-20)

Fibrocystic mastopathy affects about 50 % of all women in the course of their lives. Because of subjective symptoms, the risk of malignant degeneration (5 % of all cases), and ensuing physical and psychological stress, treatment of fibrocystic mastopathy is indispensable. So far, there is no causal therapy. Most common therapeutical regimens are associated with severe side effects. Therefore, the effect of treatment with an enzyme combination preparation was compared with that of placebo in a randomized double blind study in 96 patients with mastopathy over a study period of 6 weeks. At the start of the study both groups were well comparable with respect to all relevant study parameters. At the end of the study period there were significant differences regarding the parameters of effectiveness 'diameter of the largest cyst' (p = 0.003), 'subjective disturbance by symptoms' (p = 0.001) and 'cumulative score of complaints (< 0.001). As far as the number of cysts is concerned, there was no significant difference at the end of the study period (p = 0.695). Bearing in mind, however, that the initial condition was somewhat worse in the group treated with enzymes, a tendency towards better effectiveness of the enzyme combination preparation was observed with respect to this criterion, too. The difference of absolute change was significant (p = 0.008). The assessment of effectiveness by physician and patient showed clear advantages of the enzyme therapy over placebo. There was a higher number of mostly mild side effects in the enzyme group, but only stomach complaints and loose stool. Since tolerance was also comparable with that of placebo, the results obtained lead to the conclusion that the enzyme combination preparation lends itself to the symptomatic treatment of fibrocystic mastopathy. Further longer-term studies, including biopsies and determination of hormonal parameters, will clarify whether causal treatment of fibrocystic mastopathy is possible.

The epidemiology of benign breast disease.

Ernster V.L.

Epidemiol. Rev. 1981; 3: 184-202.

No abstract available.

Mastodynia due to fibrocystic disease of the breast controlled with thyroid hormone.

Estes NC.

Am J Surg 1981 Dec;142(6):764-6

Nineteen patients were evaluated for breast pain and nodularity associated with fibrocystic disease. Rapid pain relief occurred in 73 of patients, with total relief in 47 percent after daily treatment with 0.1 mg of levothyroxine. Softening of breast tissue and decreased nodularity occurred within 3 months in many patients. Three patients had elevated levels of serum prolactin before treatment, with dramatic pain relief and normalization of prolactin levels after treatment. Further trials of levothyroxine in patients with mastodynia due to fibrocystic disease appear justified.

Double-blind controlled trial of tamoxifen therapy for mastalgia.

Fentiman IS, Caleffi M, Brame K, Chaudary MA, Hayward JL.

Lancet 1986 Feb 8;1(8476):287-8

60 patients with severe mastalgia of more than 6 months' duration were randomly selected for treatment with either tamoxifen 20 mg daily or placebo for 3 months. As measured by linear analogue scoring, pain relief was achieved in 22/31 (71%) of those receiving tamoxifen and 11/29 (38%) of those taking placebo. Patients who did not respond to the first course of treatment were allocated to the alternative treatment for 3 months. Pain control was achieved in 8/12 (75%) of those receiving tamoxifen and 2/6 (33%) of those receiving placebo. The commonest side-effects were hot flushes (27% of patients receiving tamoxifen and 11% of those receiving placebo) and vaginal discharge (17% tamoxifen, 7% placebo). Side-effects caused 6 patients in each group to discontinue treatment. Tamoxifen is of value in the management of severe cyclical and non-cyclical mastalgia, and relief can be achieved without undue side-effects in the majority of patients.

A prospective study of the removal rate of imaged breast lesions by an 11-gauge vacuum-assisted biopsy probe system.

Fine RE, Israel PZ, Walker LC, Corgan KR, Greenwald LV, Berenson JE, Boyd BA, Oliver MK, McClure T, Elberfeld J. The Breast Center, 702 Canton Rd., Marietta, GA 30060, USA.

Am J Surg 2001 Oct;182(4):335-40

BACKGROUND: More than 1,000,000 breast biopsies are performed each year as a result of abnormalities identified by imaging techniques. This prospective study was designed to determine whether complete removal of the imaged evidence of an abnormal mammogram or ultrasonogram could be achieved with percutaneous image-guided procedures using an 11-gauge vacuum-assisted biopsy probe. METHODS: Forty-five women over the age of 18 years entered the study; 50 breast lesions were identified by ultrasonography or mammography. Biopsies were obtained using an 11-gauge vacuum-assisted probe. At 6 months after biopsy, ultrasonography or mammography examinations of the biopsy site were performed. RESULTS: Forty-five lesions (90%) were completely removed. At 6 months after biopsy, 82% of the sites were lesion free. The percentage of nonrecurring lesions at 6 months after surgery was inversely related to the size of the original lesion. CONCLUSION: This device allows biopsies to be successfully combined with complete removal of the imaged lesion in a one-step minimally invasive procedure.

Retinoid antagonism of estrogen-responsive transforming growth factor alpha and pS2 gene expression in breast carcinoma cells.

Fontana JA, Nervi C, Shao ZM, Jetten AM. Department of Medicine, University of Maryland Cancer Center, Baltimore.

Cancer Res 1992 Jul 15;52(14):3938-45

Exposure of MCF-7 breast carcinoma cells to estradiol results in an increase in transforming growth factor alpha (TGF-alpha) synthesis and secretion. Since TGF-alpha is a potent inducer of proliferation in MCF-7 cells, the increase in TGF-alpha production by estradiol is thought to play an important role in the estrogen stimulation of growth of these cells. Retinoic acid inhibits the proliferation of MCF-7 cells and antagonizes the estrogen stimulation of growth. Addition of retinoic acid resulted in a greater than 70% inhibition of estradiol-induced TGF-alpha synthesis and secretion in MCF-7 cells. The increase in TGF-alpha mRNA expression by estradiol was also inhibited by exposure of the cells to retinoic acid. Pretreatment of the cells with retinoic acid for 24 or 72 h caused more than 50 and 90% inhibition, respectively, of the estradiol-enhanced expression of TGF-alpha mRNA. Expression of pS2 mRNA in MCF-7 cells was stimulated approximately 8-fold by estradiol. Retinoic acid treatment suppressed by greater than 80% both the basal and estradiol-induced pS2 mRNA expression. Retinoic acid modulation of the estrogen receptor gene mRNA was not responsible for the retinoic acid inhibition of the stimulation of pS2 and TGF-alpha gene expression by estradiol, since estrogen receptor gene expression was increased rather than decreased in the presence of retinoic acid. The nuclear retinoic acid receptors alpha and gamma mRNA were expressed in MCF-7 cells and its retinoic acid-resistant derivative RROI. Addition of estradiol to MCF-7 cells resulted in a decreased expression of retinoic acid receptor gamma mRNA; this reduction is prevented by the presence of retinoic acid. These results indicate that retinoic acid can inhibit estradiol-induced TGF-alpha and pS2 mRNA expression in MCF-7 cells. The suppression of TGF-alpha expression may represent one possible mechanism by which retinoic acid antagonizes the stimulation of MCF-7 proliferation by estradiol.

Intake of macronutrients and risk of breast cancer.

Franceschi S, Favero A, Decarli A, Negri E, La Vecchia C, Ferraroni M, Russo A, Salvini S, Amadori D, Conti E, et al. Servizio di Epidemiologia, Centro di Riferimento Oncologico, Aviano, Italy.

Lancet 1996 May 18;347(9012):1351-6

BACKGROUND: The association between risk of breast cancer and dietary fat and intakes of other energy sources remains controversial. The Italian population offers special opportunities to assess the influence of high intakes of unsaturated fat and starch and, because the population has low awareness of diet and cancer issues, there is less scope for recall bias. We have assessed the relations of various macronutrient intakes with risk of breast cancer. METHODS: In this case-control study, 2569 women with incident breast cancer (median age 55 years) and 2588 control women (median age 56 years) in hospital with acute, non-neoplastic diseases, were interviewed in six different areas of Italy between 1991 and 1994. A validated food-frequency questionnaire was used. It included questions on 78 foods and recipes grouped into six sections, as well as specific questions on individual fat intake pattern. FINDINGS: The risk of breast cancer decreased with increasing total fat intake (trend p 0.01) whereas the risk increased with increasing intake of available carbohydrates (trend p = 0.002). The odds ratios for women in the highest compared with the lowest quintile of energy-adjusted intake were 0.81 for total fat and 1.30 for available carbohydrates. Starch was the chief contributor to the positive association with available carbohydrates. High intakes of polyunsaturated and unsaturated fatty acids (i.e., polyunsaturated fatty acids plus oleic acid) were associated with a decreased risk of breast cancer (odds ratios for highest vs lowest quintile 0.70 and 0.74, respectively). Conversely, the intakes of saturated fatty acids, protein, and fibre were not significantly associated with breast-cancer risk. INTERPRETATION: This case-controls study shows that unsaturated fatty acids protect against breast cancer, possibly because intake of these nutrients is closely correlated with a high intake of raw vegetables. The findings also suggest a possible risk in southern European populations, of reliance on a diet largely based on starch.

Plasma fatty acid profiles in benign breast disorders.

Gateley CA, Maddox PR, Pritchard GA, Sheridan W, Harrison BJ, Pye JK, Webster DJ, Hughes LE, Mansel RE. University Department of Surgery, University of Wales College of Medicine, Cardiff, UK.

Br J Surg 1992 May;79(5):407-9

Breast pain (mastalgia) and macroscopic breast cysts present commonly. Mastalgia may be improved by dietary manipulation to reduce saturated fat or supplement essential fatty acid intake. Fatty acid profiles were measured in women with mastalgia and breast cysts, before and during treatment with evening primrose oil, a rich source of essential fatty acids. The fatty acid profiles of both groups of patients were abnormal, with increased proportions of saturated fatty acids and reduced proportions of essential fatty acids. Treatment with evening primrose oil improved the fatty acid profiles towards normal, but this was not necessarily associated with a clinical response.

Management of cyclical breast pain.

Gateley CA, Mansel RE. University of Wales College of Medicine, Cardiff.

Br J Hosp Med 1990 May;43(5):330-2

Cyclical breast pain or mastalgia occurs in up to 70% of the female population. After exclusion of breast cancer and proper reassurance, only 15% of patients initially presenting will require drug treatment. Using bromocriptine, danazol and evening primrose oil some 77% of patients treated can obtain useful relief of their symptoms.

Management of the painful and nodular breast.

Gateley CA, Mansel RE. University Department of Surgery, University Hospital of South Mancheser, UK.

Br Med Bull 1991 Apr;47(2):284-94

Mild breast pain and nodularity are common and may be considered normal. Only when symptoms are severe enough to affect the patient's lifestyle should drug treatment be considered. Using danazol, bromocriptine or evening primrose oil a clinically useful improvement in pain can be anticipated in 77% of patients with cyclical mastalgia and 44% with non-cyclical mastalgia. Benign nodularity should not be biopsied surgically as it is unnecessary and makes subsequent assessment of the breast difficult.

Iodine replacement in fibrocystic disease of the breast.

Ghent WR, Eskin BA, Low DA, Hill LP. Department of Surgery, Queen's University, Hotel Dieu Hospital, Kingston, Ont.

Can J Surg 1993 Oct;36(5):453-60

OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine replacement therapy. DESIGN: Review of three clinical studies beginning in 1975: an uncontrolled study with sodium iodide and protein-bound iodide; a prospective, control, crossover study from iodide to molecular iodine; and a prospective, control, double-blind study with molecular iodine. SETTING: University affiliated breast-treatment clinics. PATIENTS: Study 1: 233 volunteers received sodium iodide for 2 years and 588 received protein-bound iodide for 5 years. Study 2: the treatment of 145 patients from study 1 treated with protein-bound iodide for several months who still had symptoms was switched to molecular iodine 0.08 mg/kg; 108 volunteers were treated initially with molecular iodine. Study 3: 23 patients received molecular iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable dye and quinine. The numbers in study 2 increased over the review period so that 1365 volunteers were being treated with molecular iodine by 1989. INTERVENTIONS: All patients in study 3 had pre- and post-treatment mammography and measurement of serum triiodothyronine, thyroxine and thyroid-stimulating hormone levels. MAIN OUTCOME MEASURES: Subjective evaluation--freedom from pain--and objective evaluation--resolution of fibrosis. RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical improvement in their breast disease, but the rate of side effects was high; 40% of patients treated with protein-bound iodide had clinical improvement. Study 2: 74% of patients in the crossover series had clinical improvement, and objective improvement was noted in 72% of those who received molecular iodine initially. Study 3: in the treatment group 65% had subjective and objective improvement; in the control group there was a subjective placebo effect in 33% and an objective deterioration of 3%. CONCLUSIONS: The fibrocystic breast reacts differently to sodium iodide, protein-bound iodide and molecular iodine. Molecular iodine is nonthyrotropic and was the most beneficial.

Effect of diet on excretion of estrogens in pre- and postmenopausal women.

Goldin BR, Adlercreutz H, Dwyer JT, Swenson L, Warram JH, Gorbach SL.

Cancer Res 1981 Sep;41(9 Pt 2):3771-3

Fecal, urinary, and plasma estrogens and plasma androgens were studied in healthy pre- and postmenopausal vegetarian and omnivorous women. Dietary histories of the subjects revealed that omnivores consumed a higher percentage of total protein and fat from animal sources. The total 72-hr fecal excretion as measured by dry weight was higher for vegetarians. Preliminary results indicate that vegetarian women excrete 2 to 3 times more estrogens in feces than do omnivores and that omnivores have about 50% higher mean plasma level of unconjugated estrone and estradiol than vegetarians. Estriol-3-glucuronide, a compound that is formed upon reabsorption of free estriol from the intestine, is found in lower concentrations in the urine of vegetarians. These data suggest that in vegetarians a greater amount of the biliary estrogens escape reabsorption and are excreted with the feces. The differences in estrogen metabolism may explain the lower incidence of breast cancer in vegetarian women.

Estrogen excretion patterns and plasma levels in vegetarian and omnivorous women.

Goldin BR, Adlercreutz H, Gorbach SL, Warram JH, Dwyer JT, Swenson L, Woods MN.

N Engl J Med 1982 Dec 16;307(25):1542-7

We studied 10 vegetarian and 10 nonvegetarian premenopausal women on four occasions approximately four months apart. During each study period, the participants kept three-day dietary records, and estrogens were measured in plasma, urinary, and fecal samples. Vegetarians consumed less total fat than omnivores did (30 per cent of total calories, as compared with 40 per cent) and more dietary fiber (28 g per day, as compared with 12 g). There was a positive correlation between fecal weight and fecal excretion of estrogens in both groups (P less than 0.001), with vegetarians having higher fecal weight and increased fecal excretion of estrogens. Urinary excretion of estriol was lower in vegetarians (P less than 0.05), and their plasma levels of estrone and estradiol were negatively correlated with fecal excretion of estrogen (P = 0.005). Among the vegetarians the beta-glucuronidase activity of fecal bacteria was significantly reduced (P = 0.05). We conclude that vegetarian women have an increased fecal output, which leads to increased fecal excretion of estrogen and a decreased plasma concentration of estrogen.

Fibrocytic breast disease: current status of diagnosis and treatment.

Greenblatt RB; Vasquez J; Samaras C

Postgrad Med (UNITED STATES) Mar 1982, 71 (3) p159-63, 166-8

Improved diagnostic procedures and use of a new steroidal agent, danazol (Danocrine), should reduce the need for surgical intervention in fibrocystic breast disease. Thermography, a non-invasive procedure that may be used with impunity, may help identify women at high risk. Mammography, which is useful in revealing malignancy in an early stage, should be done in women with tow consecutive abnormal thermograms. Biopsies should be performed, however, on suspicious, firm, irregular masses, regardless of results on thermography or mammography. Use of danazol may be advantageous not only in ameliorating pain and eliminating nodosities, but also in guiding the surgeon to the nodule that is unresponsive to treatment and therefore should be evaluated by biopsy.

Extrahepatic biliary obstruction: can silymarin protect liver function?

Hagymasi K, Kocsis I, Lugasi A, Feher J, Blazovics A. 2nd Department of Internal Medicine, Semmelweiss University, Szentkiralyi u 26, H-1088 Budapest, Hungary. hkriszti@bel2.sote.hu

Phytother Res 2002 Mar;16 Suppl 1:S78-80

The hepatoprotective property of silymarin is well known. However, it is not known whether the antioxidant silymarin might have a beneficial effect in extrahepatic cholestasis in common bile duct ligated rats. Malonaldehyde property concentrations, the hydrogen-donating ability and reducing power were measured in liver homogenates by spectrophotometry, as well as free SH-group levels and glutathione-reductase activities in sera. The total scavenger capacity of the livers was quantified by a chemiluminometric method. The elevated lipid peroxidation and decreased antioxidant capacity of liver homogenates and sera could be observed in ligated rats. Silymarin pretreatment improved the antioxidant capacity of the liver, diminished the direct bilirubin concentration and caused an increase of liver enzyme activities compared with the groups without treatment. These effects of silymarin suggest that it may be a useful agent for improving the antioxidant defensive system in extrahepatic

Breast cancer.

Henderson, M., Pike, M.C., Bernstein, L., Ross, R.K.

In Cancer Epidemiology and Prevention, Second Edition 1996. Schottenfeld, D., Fraumeni, J.F., Eds. New York: Oxford University Press.

Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.

Horner NK, Lampe JW. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.

J Am Diet Assoc 2000 Nov;100(11):1368-80

Fibrocystic breast conditions, formerly referred to as fibrocystic breast disease, affect about half of all women and typically present as any combination of breast nodularity, swelling, and pain. We reviewed the literature to evaluate evidence supporting nutrition interventions commonly recommended for fibrocystic breast conditions by health care providers. Randomized, controlled studies of the effectiveness of caffeine restriction fail to support any benefit in fibrocystic breast conditions. Similarly, evidence supporting evening primrose oil, vitamin E, or pyridoxine as treatments for the discomforts of fibrocystic breast conditions is insufficient to draw conclusions about effectiveness. Dietary alterations that influence the intermediate markers for fibrocystic breast conditions include low-fat (15% to 20% energy), high-fiber (30 g/day), and soy isoflavone regimens. However, our findings provide no solid evidence for secondary prevention or treatment of fibrocystic breast conditions through a dietary approach. Health care providers should limit recommendations to proven diet therapies supported by randomized, placebo-controlled trials, given the instability inherent in fibrocystic breast conditions and the near 20% placebo effect associated with intervention. Because excessive estrogen or altered sensitivity to estrogen is the dominant theory of etiology, interventions that may modulate endogenous steroid hormones warrant further investigation as potential treatments for symptomatic fibrocystic breast conditions.

Waist circumference, waist:hip ratio, and risk of breast cancer in the Nurses' Health Study.

Huang Z, Willett WC, Colditz GA, Hunter DJ, Manson JE, Rosner B, Speizer FE, Hankinson SE. Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.

Am J Epidemiol 1999 Dec 15;150(12):1316-24

This study examined prospectively the associations of waist circumference and waist:hip circumference ratio with risk of breast cancer. A total of 47,382 US registered nurses who reported their waist and hip circumferences in 1986 were followed up through May 1994 for identification of incident cases of breast cancer. During 333,097 person-years of follow-up, 1,037 invasive breast cancers were diagnosed. In proportional hazards analyses, waist circumference was nonsignificantly related to risk of premenopausal breast cancer but was significantly associated with postmenopausal breast cancer after adjustment for established breast cancer risk factors (for the highest quintile of waist circumference vs. the lowest, relative risk (RR) = 1.34; 95% confidence interval (CI): 1.05, 1.72). When the analysis was limited to postmenopausal women who had never received hormone replacement therapy, a stronger positive association was found (RR = 1.88; 95% CI: 1.25, 2.85). After the data were further controlled for body mass index, the positive association was only slightly attenuated (RR = 1.83; 95% CI: 1.12, 2.99). Among past and current postmenopausal hormone users, no significant associations were found. Similar but slightly weaker associations were observed between waist:hip ratio and breast cancer risk. These data suggest that greater waist circumference increases risk of breast cancer, especially among postmenopausal women who are otherwise at lower risk because of never having used estrogen replacement hormones.

Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects.

Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J. Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, USA.

J Lipid Res 2000 Apr;41(4):595-604

We previously reported that a eucaloric, low fat, liquid formula diet enriched in simple carbohydrate markedly increased the synthesis of fatty acids in lean volunteers. To examine the diet sensitivity of obese subjects, 7 obese and 12 lean volunteers were given two eucaloric low fat solid food diets enriched in simple sugars for 2 weeks each in a random-order, cross-over design (10% fat, 75% carbohydrate vs. 30% fat, 55% carbohydrate, ratio of sugar to starch 60:40). The fatty acid compositions of both diets were matched to the composition of each subject's adipose tissue and fatty acid synthesis measured by the method of linoleate dilution in plasma VLDL triglyceride. In all subjects, the maximum % de novo synthesized fatty acids in VLDL triglyceride 3;-9 h after the last meal was higher on the 10% versus the 30% fat diet. There was no significant difference between the dietary effects on lean (4313 vs. 1213%) and obese (3715 vs. 66%) subjects, despite 2-fold elevated levels of insulin and reduced glucagon levels in the obese. Similar results were obtained for de novo palmitate synthesis in VLDL triglyceride measured by mass isotopomer distribution analysis after infusion of [(13)C]acetate. On the 10% fat diet, plasma triglycerides (fasting and 24 h) were increased and correlated with fatty acid synthesis. Triglycerides were higher when fatty acid synthesis was constantly elevated rather than having diurnal variation.Thus, eucaloric, solid food diets which are very low in fat and high in simple sugars markedly stimulate fatty acid synthesis from carbohydrate, and plasma triglycerides increase in proportion to the amount of fatty acid synthesis. However, this dietary effect is not related to body mass index, insulin, or glucagon levels.

Biochemical and anthropometric characterization of morbid obesity in a large Utah pedigree.

Hunt SC, Williams RR, Adams TD. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, USA.

Obes Res 1995 Sep;3 Suppl 2:165S-172S

A Utah family with morbid obesity was extended to include 122 persons in four generations for the purpose of characterizing anthropometric and biochemical variables in family members with and without morbid obesity. Seventy-seven subjects had blood drawn for biochemical analyses. Of the 77 subjects, 12 were morbidly obese (&gt; or = 44.5 kg or 100 pounds overweight), 20 were between 22.5-45.4 kg (50 and 99 pounds) overweight and 45 were less than 22.5 kg (50 pounds) overweight. Sixty-two randomly-ascertained controls were used for comparisons of age- and gender-adjusted study variables. Morbidly obese subjects had mean body mass indices (BMI) of 41.0 kg/m2 (62 kg over ideal weight) compared to 25.3 kg/m2 (10 kg overweight) in the &lt; 22.5 kg family members (p &lt; 0.001). The &lt; 22.5 kg family members had lower BMI than the random controls (27.6 kg/m2, p &lt; 0.05), indicating clear bimodality of obesity within the pedigree. Percent body fat from bioelectrical impedance was 35% versus 24% in the morbidly obese and the &lt; 22.5 kg subjects, respectively. Idealbody weight was similar among the three pedigree weight groups. Hip and waist circumferences were much larger in the morbidly obese and the waist-to-hip ratio remained significantly greater in the morbidly obese subjects compared to the &lt; 22.5 kg group. Morbidly obese subjects had elevated triglycerides and VLDL-C levels, low HDL-levels, and normal LDL-C levels. Fasting insulin was the best predictor of morbid obesity of all biochemical and lipid measurements (odds ratio of 4.5). Fasting insulin levels and the insulin-to-glucose ratio were more than twice as high as control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence, Screening and Management of Atypical Hyperplasia and Lobular Carcinoma In Situ 1997.

Hurley, S.F., Hart, S., Susil, B.

Canberra: National Health and Medical Research Council/National Breast Cancer Centre.

Breast health (non-cancerous breast issues).

Imaginis.

Imaginis Newsletter 2000 Nov 13.

Durham, NC: Imaginis Corporation.

Soy and breast cancer.

Imaginis.

Imaginis Newsletter 2001 Jan 20.

Durham, NC: Imaginis Corporation.

Relation between the serum level of C-peptide and risk factors for coronary heart disease and diabetic microangiopathy in patients with type-2 diabetes mellitus.

Inukai T, Matsutomo R, Tayama K, Aso Y, Takemura Y. Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Japan.

Exp Clin Endocrinol Diabetes 1999;107(1):40-5

Syndrome X is used to describe a constellation of factors that lead to coronary heart disease (CHD): hypertension, hyperinsulinemia, impaired glucose tolerance, and an abnormality in lipid metabolism. We investigated the relationship between serum levels of C-peptide immunoreactivity (CPR) and diabetic complications in 256 patients with type-2 diabetes mellitus. The serum level of CPR was measured by radioimmunoassay (RIA). Diabetic patients were divided into 3 groups according to the serum level of CPR as follows: low CPR (n = 19, &lt;0.7 ng/ml), normal CPR (n = 174, 0.7 to 2.2 ng/ml) and high CPR (n = 63, &gt;2.2 ng/ml). The body mass index (BMI) and the serum level of triglycerides were significantly higher in the high CPR group (P &lt; 0.05, respectively) compared with normal CPR group. The prevalence of hypertension was significantly higher in the high CPR group than in the other 2 groups (low CPR: 16%, normal CPR: 28%, high CPR: 38%). The frequency of the number of patients receiving insulin therapy was greater in the low CPR group than in the other 2 groups, (low CPR: 58%, normal CPR: 15%, high CPR: 11%). The serum CPR level was significantly lower in patients with than without proliferative retinopathy or macroalbuminuria. Our conclusion is that the present data suggest that an increased serum level of CPR is associated with obesity, elevated serum triglycerides, and hypertension in patients with type-2 diabetes mellitus. A low CPR level leading to hyperglycemia is associated with the progression of diabetic microangiopathies, such as retinopathy and nephropathy.

Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture.

Ip MM, Masso-Welch PA, Shoemaker SF, Shea-Eaton WK, Ip C. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA. mip@sc3101.med.buffalo.edu

Exp Cell Res 1999 Jul 10;250(1):22-34

The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, betaII, delta, varepsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, varepsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis. Copyright 1999 Academic Press.

Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats.

Ip C, Banni S, Angioni E, Carta G, McGinley J, Thompson HJ, Barbano D, Bauman D. Department of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

J Nutr 1999 Dec;129(12):2135-42

Conjugated linoleic acid (CLA) is a potent cancer preventive agent in animal models. To date, all of the in vivo work with CLA has been done with a commercial free fatty acid preparation containing a mixture of c9,t11-, t10,c12- and c11,t13-isomers, although CLA in food is predominantly (80-90%) the c9,t11-isomer present in triacylglycerols. The objective of this study was to determine whether a high CLA butter fat has biological activities similar to those of the mixture of free fatty acid CLA isomers. The following four different endpoints were evaluated in rat mammary gland: 1) digitized image analysis of epithelial mass in mammary whole mount; 2) terminal end bud (TEB) density; 3) proliferative activity of TEB cells as determined by proliferating cell nuclear antigen immunohistochemistry; and 4) mammary cancer prevention bioassay in the methylnitrosourea model. It should be noted that TEB cells are the target cells for mammary chemical carcinogenesis. Feeding butter fat CLA to rats during the time of pubescent mammary gland development reduced mammary epithelial mass by 22%, decreased the size of the TEB population by 30%, suppressed the proliferation of TEB cells by 30% and inhibited mammary tumor yield by 53% (P &lt; 0.05). Furthermore, all of the above variables responded with the same magnitude of change to both butter fat CLA and the mixture of CLA isomers at the level of CLA (0.8%) present in the diet. Interestingly, there appeared to be some selectivity in the uptake or incorporation of c9,t11-CLA over t10,c12-CLA in the tissues of rats given the mixture of CLA isomers. Rats consuming the CLA-enriched butter fat also consistently accumulated more total CLA in the mammary gland and other tissues (four- to sixfold increases) compared with those consuming free fatty acid CLA (threefold increases) at the same dietary level of intake. We hypothesize that the availability of vaccenic acid (t11-18:1) in butter fat may serve as the precursor for the endogenous synthesis of CLA via the Delta9-desaturase reaction. Further studies will be conducted to investigate other attributes of this novel dairy product.

Stereotactic histologic biopsy in breasts with implants.

Jackman RJ, Lamm RL. Department of Radiology, Palo Alto Medical Clinic, 795 El Camino Real, Palo Alto, CA 94301. From the 1999 RSNA scientific assembly. Received January 4, 2001.

Radiology 2002 Jan;222(1):157-64

PURPOSE: To describe our experience with stereotactic histologic biopsy in patients with breast implants. MATERIALS AND METHODS: Thirty-one (1.3%) of 2,399 consecutive lesions on which stereotactic histologic biopsy was performed were in breasts containing implants. Biopsy difficulties were evaluated for lesions in breasts with and breasts without implants. Biopsy was performed on lesions in patients with implants prone on a dedicated table, with automated large-core (n = 13) or directional vacuum-assisted (n = 18) devices. Follow-up was surgical (11 of 11 malignancies and two of three high-risk lesions) and mammographic (one of three high-risk lesions and 17 of 17 benign lesions). RESULTS: There were no implant ruptures, hematomas requiring drainage, infections requiring treatment, false-negative findings, or histologic underestimations. Difficulties with stereotactic histologic biopsy were more prevalent in breasts with implants and included positioning problems in 10 (50%) of 20 lesions in breasts with subglandular implants and zero (0%) of 10 with subpectoral implants, lesions seen on only one view in four (13%) of 31 lesions, specimen radiographs negative for calcifications in two (10%) of 20 lesions, prominent bleeding in two (6%) of 31 lesions, and suboptimally small tissue samples in three (10%) of 31 lesions. CONCLUSION: Stereotactic histologic biopsy is safe in breasts with implants. Compared with that in breasts without implants, biopsy is often technically more difficult and may eventually prove less accurate.

Fish consumption and breast cancer risk: an ecological study.

Kaizer L, Boyd NF, Kriukov V, Tritchler D. Ludwig Institute for Cancer Research (Toronto Branch), Ontario, Canada.

Nutr Cancer 1989;12(1):61-8

There is experimental evidence that fish oils protect against mammary carcinogens in animals. However, there has been little investigation of the possible relevance of this finding to breast cancer in humans. We compared breast cancer incidence and mortality rates with estimates of the consumption of fish and other foods and nutrients in the countries for which reliable data are available. The results showed an inverse association between percent calories from fish and breast cancer rates that was consistent with a protective effect. This analysis confirmed the finding of others that dietary fat is strongly associated with international variation in breast cancer rates. It also showed that of the dietary components considered, percent calories from fish was the factor most strongly correlated with breast cancer rates after statistical adjustment for dietary fat intake. This result is therefore in accord with animal experimental data and suggests that the omega-3 fatty acids contained in certain fish may protect against breast cancer.

The deadly quartet. Upper-body obesity, glucose intolerance, hpertriglyceridemia, and hypertension.

Kaplan NM. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9030.

Arch Intern Med 1989 Jul;149(7):1514-20

The contribution of obesity to cardiovascular risk has not been adequately appreciated because of a failure to recognize the involvement of upper-body predominance of body weight with hypertension, diabetes, and hypertriglyceridemia even in the absence of significant overall obesity. This article examines the evidence that upper-body obesity, as usually induced by caloric excess in the presence of androgens, mediates these problems by way of hyperinsulinemia. Because of these interrelationships, there is a need to identify and prevent upper-body obesity or, failing that, to provide therapies that will control the associated problems without aggravating hyperinsulinemia.

Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats.

Kimura M, Tanaka S, Yamada Y, Kiuchi Y, Yamakawa T, Sekihara H. The Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan.

Endocrinology 1998 Jul;139(7):3249-53

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age-and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.

Antioxidant properties of silybin glycosides.

Kosina P, Kren V, Gebhardt R, Grambal F, Ulrichova J, Walterova D. Centre for Bioanalytical Research, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.

Phytother Res 2002 Mar;16 Suppl 1:S33-9

New soluble derivatives of the hepatoprotective flavonolignan silybin (1), namely silybin galactoside (2), glucoside (3), lactoside (4) and maltoside (5) were investigated for their radical scavenging and antilipoperoxidation properties. According to cyclic voltammetry the results show that glycosides are weaker electron donors than silybin, although it was of interest that they were found to be more potent scavengers of the 1,1-diphenyl-2-picrylhydrazyl and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)-derived radicals. The glycosides (2)-(5) were more efficient than silybin in preventing tert-butylhydroperoxide-induced lipoperoxidation of rat liver mitochondrial membranes. Furthermore, glycosides (2)-(5) were significantly more cytoprotective than silybin in tert-butylhydroperoxide-damaged rat erythrocytes and primary hepatocyte cultures. Glycosylation of silybin substantially reduced its toxic effects in primary cultured hepatocytes observed during prolonged incubation. These results suggest that silybin glycosides are suitable soluble derivatives of silybin for experimental studies and may have therapeutic potential. Copyright 2002 John Wiley &amp;amp; Sons, Ltd.

Prolactin response to thyrotropin-releasing hormone stimulation and dopaminergic inhibition in benign breast disease.

Kumar S, Mansel RE, Hughes LE, Woodhead JS, Edwards CA, Scanlon MF, Newcombe RG.

Cancer 1984 Mar 15;53(6):1311-5

Pituitary function was tested in predefined clinical groups of benign breast disease under strictly controlled clinical and laboratory conditions. Two different tests of prolactin storage and control mechanisms, direct stimulation by thyrotropin-releasing hormone (TRH) and inhibition of dopaminergic control by domperidone, indicate a significant abnormality in patients with severe cyclical mastalgia and nodular breast disease (P less than 0.05 and P less than 0.002), but not in those with noncyclical mastalgia. No abnormalities of thyroid function were found.

Prediction of response to endocrine therapy in pronounced cyclical mastalgia using dynamic tests of prolactin release.

Kumar S, Mansel RE, Hughes LE, Edwards CA, Scanlon MF.

Clin Endocrinol (Oxf) 1985 Dec;23(6):699-704

Many of the endocrine agents currently used to treat symptomatic benign breast disease modify the action or secretion of prolactin. We have compared the responses to hormonal therapy with dynamic assessment of prolactin control in 29 patients with cyclical mastalgia and in 7 patients with non-cyclical mastalgia. The tests of prolactin release used were direct stimulation by TRH or dopaminergic blockade by domperidone. These were carried out before treatment in the mastalgic patients and also in 22 age-matched asymptomatic controls. The response to treatment was assessed using a special pain chart and visual linear analogue scale. Patients with cyclical mastalgia could be divided into two groups: those in whom the peak prolactin release was exaggerated (greater than 4000 mU/l) and those in whom the prolactin release was less marked and similar to control subjects and patients with non-cyclical mastalgia. Patients in the cyclical mastalgia group with a high peak prolactin release responded to hormonal treatment significantly more frequently (90%) than those with a normal prolactin release (50%). Basal prolactin levels did not correlate with the response to treatment. In the non-cyclical mastalgia group, no patient had peak prolactin release greater than 4000 mU/l and none responded to therapy. This study indicates that dynamic tests of prolactin release in cyclical mastalgia may be useful in predicting the subsequent satisfactory response to endocrine therapy if a high peak prolactin release is induced.

The effect of dehydroepiandrosterone combined with a low-fat diet in spontaneously obese dogs: a clinical trial.

Kurzman ID, Panciera DL, Miller JB, MacEwen EG. Department of Medical Sciences, University of Wisconsin, School of Veterinary Medicine, Madison 53706, USA.

Obes Res 1998 Jan;6(1):20-8

Dehydroepiandrosterone (DHEA) has been shown to have antiobesity activity in rodents and spontaneously obese dogs. This study evaluated the effect of DHEA or placebo combined with a low-fat/high-fiber diet in spontaneously obese dogs in a clinical trial. Spontaneously obese, euthyroid dogs, referred to the University of Wisconsin School of Veterinary Medicine for treatment of their obesity, were evaluated for percent overweight, rate of weight loss, serum cholesterol, plasma lipoprotein and serum biochemistry profiles, complete blood count, and endocrine profiles (T4, T3, cortisol, insulin, and DHEA-sulfate). DHEA-treated dogs had a significantly increased rate of actual and percent excess weight loss compared with placebo-treated dogs. Serum cholesterol decreased in both treatment groups; however, DHEA-treated dogs had a significantly greater reduction than placebo-treated dogs. DHEA-treated dogs had a significant 32% reduction in total plasma cholesterol, which was due to a 27% reduction in the lipoprotein fraction containing the high-density lipoprotein (HDL) and a 50% reduction in the lipoprotein fraction containing the low-density lipoprotein (LDL). Placebo-treated dogs did not have a significant reduction in total plasma cholesterol or in the fraction containing LDL; however, they did have a significant 11% reduction in the fraction containing HDL. Significant decreases in serum T4 and T3 observed in dogs receiving DHEA were not noted in dogs receiving placebo. DHEA in combination with caloric restriction results in a faster rate of weight loss than does caloric restriction alone. In addition, DHEA has hypocholesterolemic activity, particularly affecting the lipoprotein fraction containing the LDL cholesterol.

The Woman's Health Companion 1996.

Lark, S.M.

Berkeley, CA: Celestial Arts.

Benign breast disease and consumption of beverages containing methylxanthines.

La Vecchia C, Franceschi S, Parazzini F, Regallo M, Decarli A, Gallus G, Di Pietro S, Tognoni G.

Natl Cancer Inst 1985 May;74(5):995-1000

The relationship between methylxanthine (Mx) consumption and benign breast disease was evaluated in a case-control study of 288 women with histologically confirmed benign breast lumps (203 dysplastic lesions and 85 benign tumors) and 2 groups of control women--285 patients in the hospital for acute conditions apparently unrelated to the consumption of Mx-containing beverages and 291 outpatients. The relative risk estimates of dysplastic breast lesions (fibrocystic disease), with allowance for all identified potential distorting factors, for women who drank 1-2 or 3 or more cups of coffee per day were 4.1 and 6.4, respectively, when the hospital controls were the comparison group and 2.0 and 3.7, respectively, when the outpatient controls were the comparison group. The relationship was even stronger when the total consumption of Mx-containing beverages (coffee plus tea) was considered and increased with increasing duration of use. The association was not explained by any of the major risk factors for fibrocystic breast diseases or by differences in general characteristics or other lifestyle habits between cases and controls. Mx consumption was not related to the risk of benign breast tumors (fibroadenomas). These findings support the hypothesis that Mx consumption is related to the risk of dysplastic lesions of the breast.

Cholesterol and bile acid metabolism in obesity.

Leijd B.

Clin Sci (Lond). 1980 Sep;59(3):203-6.

1. The present study was undertaken to determine the influence of obesity on bile acid kinetics and cholesterol balance in man. 2. Fourteen obese and normolipidaemic patients (160 +/- 6% of ideal body weight, mean +/- SEM) were studied under standardized dietary conditions. Bile acid kinetics, were determined with the aid of 14C-labelled cholic acid and chenodeoxycholic acid. Cholesterol balance was calculated as the sum of bile acid synthesis plus daily faecal excretion of neutral C27 steroids minus dietary intake of cholesterol. The results obtained were compared with previously published data on control subjects (n = 13). 3. The cholesterol balance was higher in the obese patients (2.61 +/- 0.27 mmol/day) than in the control subjects (1.78 +/- 0.22 mmol/day), owing to a higher excretion of neutral steroids. When expressed per kg of body weight the cholesterol balance was quite normal in the obese patients.

[Hormonal contraception and benign breast disease. Evaluation of a treatment protocol for chronic mastopathy with mastalgia] [Article in Italian]

Leonardi M. Divisione di Ginecologia e Ostetricia, Azienda USSL Ambito Territoriale N. 14, Presidio Ospedaliero di Iseo (Brescia).

Minerva Ginecol 1997 Jun;49(6):271-6

INTRODUCTION AND AIMS: The aim of this study was to study patients suffering from mammary nodules, fibrocystic disease and mastodynia. Having established the absence of malignant disease, the effect of EP (oestroprogestin) was evaluated in the treatment of fibrocystic disease with mastalgia.

METHODS: From January 1990 to December 1995 a total of 1921 women underwent breast examination at the "Centro di Fisiopatologia della Mammella" in the Division of Gynecology and Obstetrics of Iseo Municipal Hospital. Subjects were aged between 9 and 84 years old. The experimental protocol included a retrospective study of a group of 89 patients suffering from chronic fibrocystic disease with mastalgia with a 3-month follow-up. The clinical examination was commenced by recording the patient's history and the measurement of the thickness of the gland and the evaluation of mastalgia represented important stages of the eco-clinical assessment. The setting for the study was the breast pathology out-patient clinic of the Division of Gynecology and Obstetrics. These women regularly attended our outpatient clinics for the following reasons: depistage, mastodynia, mammary secretion, self-diagnosis of mammary nodules, checkups in patients during follow-up after surgery for genital neoplasia. All patients underwent clinical, echographic and often mammography/X-ray. Patients were selected on the basis of the following criteria: absence of malignant pathology and presence of chronic fibrocystic disease with mastalgia. Of those admitted to the study (no. = 89), only 59 completed the course. In addition to the absence of malignant pathology and the presence of chronic fibrocystic disease with mastalgia, the following parameters were assessed: measurement of the thickness of the mammary gland involving QSE before and after 3-month treatment with EP. The EP used were: gestodene 0.075 mg and etynylestradiol 0.03 mg-Minulet, or etynylestradiol 0.02 mg and dexogestrel 0.150 mg-Securgin and Mercilon.

RESULTS: The response to treatment was classified according to the 4 levels of the Cardiff Breast Score (CBS). The results were relatively good: 35.59% of patients showed a reduction in symptoms; 25.42% showed a marked improvement, and 18.64% a remission of symptoms. No effect was reported in 20.33% of patients.

CONCLUSIONS: In conclusion, it may be said that EP treatment for 3 months can at least be proposed in patients with chronic fibrocystic disease and mastalgia given that a reduction and improvement in symptoms was seen in 60% of patients.

DHEA(S): the fountain of youth.

Leowattana W. Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

J Med Assoc Thai 2001 Oct;84 Suppl 2:S605-12

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.

The effect of vitamin E on mammary dysplasia: a double-blind study.

London RS, Sundaram GS, Murphy L, Manimekalai S, Reynolds M, Goldstein PJ.

Obstet Gynecol 1985 Jan;65(1):104-6

Alpha-tocopherol (vitamin E) has been used to treat patients with benign breast disease. To evaluate the efficacy of this treatment, a randomized, double-blind placebo-controlled study was performed on 128 women with confirmed mammary dysplasia. Patients were treated with placebo or 150, 300, or 600 IU of d, 1 alpha-tocopherol per day for two months; breast examinations, sonography, and thermography were performed in the midluteal phase of the menstrual cycle before and after treatment. No significant objective effects to treatment were noted in any of the parameters monitored. In addition, serum concentrations of estradiol, progesterone, dehydroepiandrosterone sulfate, and testosterone were measured before and after treatment. There were no significant effects on concentrations of these hormones. From this study, d, 1 alpha-tocopherol does not seem to be beneficial in the treatment of patients with mammary dysplasia.

Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia.

London RS, Sundaram GS, Schultz M, Nair PP, Goldstein PJ.

Cancer Res 1981 Sep;41(9 Pt 2):3811-3

Patients with mammary dysplasia (17 patients) and controls (6 patients) were treated in a double-blind study with alpha-tocopherol acetate (600 units/day). Determination of serum alpha-tocopherol, estradiol, estriol., and progesterone were made from blood samples collected on Day 21 of the menstrual cycle before and during therapy. Eight-eight % of patients showed clinical response to therapy. Serum alpha-tocopherol concentrations rose after therapy in patients and controls. Serum estradiol and progesterone concentration were not statistically different in patients or controls after therapy, although patients showed a trend toward increased serum progesterone concentration. However, the ratio of progesterone to estradiol, which is abnormal in mammary dysplasia patients, rose from 30 +/- 7 (S.E.) to 53 +/- 11 in patients after alpha-tocopherol therapy (p less than 0.05). Control patients showed no significant change in progesterone/estradiol ratio. Results of this study indicate that alpha-tocopherol therapy may correct an abnormal progesterone/estradiol ratio in patients with mammary dysplasia, with implications on reducing future risk for malignant breast disease.

Treatment of breast fibrocystic disease with tanazol

Lopez S.P.; Martinez E.J.; Reillo M. M. Reillo, Servicio Obstetricia y Ginecologia, Hospital Marina Baixa, Villajoyosa, Alicante Spain

Acta Ginecologica (ACTA GINECOL.) (Spain) 1996, 53/10 (304-309)

Purpose: To assess the response of breast fibrocystic disease treated with tanazol or gestagens. Design: Retrospective and comparative study on therapy with tanazol or gestagens. Material and methods: Clinic, echographic, and mammografic features of breast fibrocystic disease were analyzed in 119 women. These patients were treated with tanazol or gestagens over 6 months at least. Conclusions: Tanazol gets complete improvement of symptoms in 25.2% of cases; partial improvement in 10.9%, and no improvement in 8.4% of them versus progestagens in 33.6%, 8.4% and 17.7% respectively. These outcomes were remarkable in patients with multiple palpable nodes of the breast. There were significant differences (p = 0.023) in these patients but no in patients with breast pain.

[Treatment of fibrocystic breast disease with lisuride] [Article in Spanish]

Lopez Rosales C, Romero Espinosa RE, Juarez Vazquez J. Hospital Dr. Dario Fernandez Fierro, ISSSTE, Mexico, D.F.

Ginecol Obstet Mex 1991 Dec;59:358-61

To study the efficacy of lisuride in fibrocystic mastopathy, we conducted a clinical trial in 23 out patients, aged 19-50 years, randomly recruited from the gynecological service of the ISSSTE, Dr. Dario Fernandez Fierro. Hospital. The only exclusion criteria was having received previous treatment. The patients clinical history was recorded. Physical examination, hormone profile (FSH, LH, prolactin, testosterone, estrogen and progesterone) and ultrasound exam of the mammae at baseline were performed in all patients, as well as, mammography in patients older than 40 years or those requiring so. Treatment was started with 1/2 tablet of lisuride (0.1 mg)/8 hours, preferably with meals, for 3 months. At the end of therapy, hormone profile, ultrasound of the mammae and physical examination were repeated for control purposes. We obtained the following results; fibrocystic mastopathy was most frequent in women aged 20-29 years, mean age 31 years symptoms disappeared in 36.9% and were reduced notably in 63.1%, of cases. Grade O ultrasound lesions disappeared in 100% of patients and grade I and II lesions improved. On physical examination all patients showed improvement; estrogen values were reduced and progesterone incremented. The prolactin level were normal at baseline, as well as by the end of treatment. One patient suffered severe side effects which required interruption of treatment; 4 patients experimenting light side effects were able to continue therapy and in the remaining 18 patients, no adverse reactions were observed.

Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens.

Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von Schoultz B. Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden.

Climacteric 2001 Mar;4(1):42-8

OBJECTIVE: The aim of this study was to evaluate the impact of different hormone replacement therapy (HRT) regimens on mammographic breast density.

STUDY DESIGN: Mammographic density was recorded in women participating in a population-based screening program. At first mammogram, all women were non-users of HRT, and thereafter reported continuous use of the same HRT regimen. The study population comprised 158 women: a total of 52 women were using continuous combined HRT (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 5 mg); 51 women were using low-dose oral estrogen alone (estriol 2 mg daily); and 55 women were using unopposed transdermal estrogen given as a patch (estradiol 50 micrograms/24 h). Films were coded and analyzed for mammographic density by an independent radiologist blinded to treatments. Mammographic density was classified according to Wolfe.

RESULTS: An increase in mammographic density was much more common among women taking continuous combined HRT (40%) than for those using oral low-dose estrogen (6%) and transdermal (2%) treatment. The increase in density was already apparent at the first visit after starting HRT. During long-term follow-up, there was very little change in mammographic status.

CONCLUSION: HRT regimens were shown to have different effects on the normal breast. There is an urgent need to clarify the biological nature and significance of a change in mammographic density during treatment and, in particular, its relation to symptoms and breast cancer risk.

Upgrade rate of core biopsy-determined atypical ductal hyperplasia by open excisional biopsy.

Maganini RO, Klem DA, Huston BJ, Bruner ES, Jacobs HK. The Breast Health Center, DuPage Medical Group, 1250 N. Mill St., Naperville, IL 60563, USA.

Am J Surg 2001 Oct;182(4):355-8

BACKGROUND: Core biopsy finding of atypical ductal hyperplasia (ADH) are generally followed by open biopsy to avoid underestimation of malignant disease.

METHODS: Retrospective examination of 11 gauge stereotactic-guided vacuum-assisted core biopsies was made with respect to ADH diagnosis, follow-up open biopsy, and upgrade rate. Readily available clinical, mammographic, and pathologic features potentially contributory to an upgrade were studied.

RESULTS: This series of 1,313 patients had 43 ADH diagnoses. Thirty-two had open follow-up. There were 4 upgrades. Mammographic indication for biopsy, age, removal of calcifications, and the percentage of ADH in the specimen were not significant in predicting an upgrade with all probabilities over 0.10, odds ratios not different than 1, and 95% bounds all encompassing 1.

CONCLUSIONS: These data indicate a high upgrade rate (13%) for ADH-positive core biopsies with no definitive predictive criteria for an upgrade. Our data support follow-up excision of ADH lesions diagnosed by core biopsy.

N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France.

Maillard V, Bougnoux P, Ferrari P, Jourdan ML, Pinault M, Lavillonniere F, Body G, Le Floch O, Chajes V. Laboratoire de Biologie des Tumeurs, Clinique d'Oncologie-Radiotherapie, Service de Gynecologie-Obstetrique, E.A. 2103, Unite de Recherche Associee Universite-INRA, CHU, Tours, France.

Int J Cancer 2002 Mar 1;98(1):78-83

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer. Copyright 2001 Wiley-Liss, Inc.

Effect of herbal teas on hepatic drug metabolizing enzymes in rats.

Maliakal PP, Wanwimolruk S. School of Pharmacy, University of Otago, Dunedin, New Zealand.

J Pharm Pharmacol 2001 Oct;53(10):1323-9

We have investigated the effect of herbal teas (peppermint, chamomile and dandelion) on the activity of hepatic phase I and phase II metabolizing enzymes using rat liver microsomes. Female Wistar rats were divided into six groups (n = 5 each). Three groups had free access to a tea solution (2%) while the control group had water. Two groups received either green tea extract (0.1%) or aqueous caffeine solution (0.0625%). After four weeks of pretreatment, different cytochrome P450 (CYP) isoforms and phase II enzyme activities were determined by incubation of liver microsomes or cytosol with appropriate substrates. Activity of CYP1A2 in the liver microsomes of rats receiving dandelion, peppermint or chamomile tea was significantly decreased (P &lt; 0.05) to 15%, 24% and 39% of the control value, respectively. CYP1A2 activity was significantly increased by pretreatment with caffeine solution. No alterations were observed in the activities of CYP2D and CYP3A in any group of the pretreated rats. Activity of CYP2E in rats receiving dandelion or peppermint tea was significantly lower than in the control group, 48% and 60% of the control, respectively. There was a dramatic increase (244% of control) in the activity of phase II detoxifying enzyme UDP-glucuronosyl transferase in the dandelion tea-pretreated group. There was no change in the activity of glutathione-S-transferase. The results suggested that, like green and black teas, certain herbal teas can cause modulation of phase I and phase II drug metabolizing enzymes.

Effects of eicosapentaenoic and gamma-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats.

Mancuso P, Whelan J, DeMichele SJ, Snider CC, Guszcza JA, Claycombe KJ, Smith GT, Gregory TJ, Karlstad MD. Life Sciences Program in Physiology, University of Tennessee, USA.

Crit Care Med 1997 Mar;25(3):523-32

OBJECTIVES: Proinflammatory eicosanoids (cyclooxgenase and lipoxygenase metabolites of arachidonic acid) released by alveolar macrophages play an important role in endotoxin-induced acute lung injury. We investigated the effect of prefeeding rats for 21 days with enteral diets that provided the anti-inflammatory fatty acids, eicosapentaenoic acid and gamma-linolenic acid (derived from fish oil and borage oil, respectively), as compared with an n-6 fatty acid-enriched diet (corn oil) on the following: a) lung microvascular protein permeability, arterial blood pressure, and platelet and white blood cells in a model of endotoxin-induced acute lung injury; b) alveolar macrophage prostaglandin and leukotriene synthesis; and c) liver and alveolar macrophage phospholipid fatty acid composition.

DESIGN: Prospective, randomized, controlled, double-blind study.

SETTING: Research laboratory at a university medical center.

SUBJECTS: Male Long-Evans rats, weighing 250 g.

INTERVENTIONS: Rats were randomized into four dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day), containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, 20% fish and 5% borage oil, or 20% fish and 20% borage oil for 21 days. On day 22, lung microvascular protein permeability, mean arterial pressure, and platelet and white blood cell counts were determined for 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg). In a second group of prefed rats, the phospholipid fatty acid composition was determined in liver and alveolar macrophages. Alveolar macrophages were harvested by bronchoalveolar lavage and stimulated in vitro with a calcium ionophore (A23187), and the concentrations of leukotrienes B4 and B5, thromboxane A2, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were measured in a third group of prefed rats.

MEASUREMENT AND MAIN RESULTS: Lung permeability was greatest with corn oil and was significantly attenuated with 20% fish oil and 20% fish and 5% borage oil, and this effect approached significance with 20% fish and 20% borage oil (p = .06). The early and late hypotensive effects of endotoxin were attenuated with 20% fish oil, 20% fish and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Concentrations of leukotriene B4, prostaglandin E2, and thromboxane B2 released from A23187-stimulated alveolar macrophages were significantly lower with 20% fish oil and 20% fish and 20% borage oil, as compared with corn oil. The increase in lung microvascular protein permeability with 20% fish and 20% borage oil was not significantly different than the lung microvascular protein permeability that was found in animals receiving 20% fish oil (p = .20) and 20% fish and 5% borage oil (p = .31). Alveolar macrophage and liver phospholipid concentrations of arachidonic acid were lower, and the concentrations of eicosapentaenoic acid and docosahexaenic acid were higher, with 20% fish oil, and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, was increased with 20% fish and 20% borage oil, as compared with 20% fish oil and 20% fish and 5% borage oil.

CONCLUSIONS: The severity of pulmonary microvascular protein permeability and the degree of hypotension were reduced with fish or fish and borage oil diets, as compared with corn oil, in endotoxic rats. The reduced synthesis of the proinflammatory arachidonic acid-derived mediators, leukotriene B4, thromboxane B2, and prostaglandin E2 from stimulated alveolar macrophages was indicative of a decrease in arachidonic acid and an increase in eicosapentaenoic acid and docosahexaenoic acid in cell membrane phospholipids.

Effects and tolerability of n-6 essential fatty acid supplementation in patients with recurrent breast cysts.

Mansel, R.E., Gateley, C.A., Harrison, B.J. et al.

J. Nutr. Med. 1990a; 1: 195-200.

No abstract available.

A randomized trial of dietary intervention with essential fatty acids in patients with categorized cysts.

Mansel RE, Harrison BJ, Melhuish J, Sheridan W, Pye JK, Pritchard G, Maddox PR, Webster DJ, Hughes LE. University Department of Surgery, Cardiff, Wales, United Kingdom.

Ann N Y Acad Sci 1990;586:288-94

Two hundred women with breast cysts proven by aspiration were entered into a randomized double-blind trial of Efamol (evening primrose oil) at a dose of 6 capsules daily or equivalent placebo dose for a year. Cysts were categorized by initial electrolyte composition, and follow-up continued for 1 year posttherapy. Recurrent cyst formation in the first year was slightly (but not significantly) lower in the Efamol group compared with the placebo-treated group. The Efamol treatment was well tolerated as the dropout rate was only 7% and equal in both the active and placebo groups. The initial electrolyte composition did not predict for cyst recurrence.

Effects of essential fatty acids on cyclical mastalgia and noncyclical breast disorders.

Mansel, R.E., Pye, J.K., Hughes, L.E.

In Omega-6 Essential Fatty Acids 1990c, pp. 557-67.

Horrobon, D., Ed. New York: Wiley-Liss.

Controlled trial of the antigonadotropin danazol in painful nodular benign breast disease.

Mansel RE, Wisbey JR, Hughes LE.

Lancet 1982 Apr 24;1(8278):928-30

In a double-blind crossover study of the effects of the antigonadotropin danazol on pain and nodularity in 28 women with cyclical mastalgia danazol was given at doses of 200 mg/day and 400 mg/day, and the responses were assessed both subjectively and objectively. Danazol caused a significant and progressive decrease in breast pain and nodularity when compared with placebo. Symptoms responded more quickly with the 400 mg/day dose of danazol than with the 200 mg dose, but the larger dose also caused greater side-effects. Danazol is a useful addition to the range of antihormones that can be used to suppress the symptoms of severe hormone-related benign breast disease.

Thyroid hormones in fibrocystic breast disease.

Martinez L, Castilla JA, Gil T, Molina J, Alarcon JL, Marcos C, Herruzo A. Department of Obstetrics and Gynecology, Virgen de las Nieves General Hospital, Granada, Spain.

Eur J Endocrinol 1995 Jun;132(6):673-6

This study was undertaken to evaluate the role of thyroid hormones in fibrocystic breast disease. The concentrations of thyroid-stimulating hormone (TSH), thyroxine (T4), free T4 and free triiodothyronine (T3) were determined in serum of 50 women with fibrocystic breast disease without macrocysts (cysts of over 3 mm diameter) and in the serum and breast cyst fluid (BCF) of 60 women with fibrocystic breast disease and macrocysts. Possible relationships between thyroid hormones and estradiol, dehydroepiandrosterone sulfate, testosterone, progesterone and 17-hydroxyprogesterone in the BCF also were analyzed. Serum thyroid hormone levels did not differ between the two groups. Free T3 levels were higher in BCF than in serum (p &lt; 0.001), whereas T4, free T4 and TSH concentrations were lower in BCF as compared to serum (p &lt; 0.001). Cysts were divided according to their K+/Na+ ratio because a ratio above 3 represents a predictor of malignant transformation. Free T3 concentrations were higher in BCF than in serum, in both low K+/Na+ cysts and in cysts with a K+/Na+ ratio above 3; those cysts with a high K+/Na+ ratio had the highest free T3 concentration. Free T3 in cysts correlated positively to the K+/Na+ ratio (r = 0.831; p &lt; 0.001). Multiple linear regression analysis demonstrated that the concentration of free T3 in BCF was predicted statistically by the positive regression coefficient for the estradiol concentration. No candidate variable was included in the model to predict concentrations of TSH, free T4 or T4 in BCF. These data suggest an important role of free T3 in the physiology of fibrocystic breast disease.

Menopause: women's sex hormones: a refresher course.

Mayo Clinic.

Mayo Clinic Women's HealthSource 2001.

Rochester, MN: Mayo Foundation for Medical Education and Research.

Phyllodes tumor of the breast.

Mazy, S., Hustin, J. Van Reepinghen, P.

J. Belge Radiol. (JBR-BTR) 1999 Jun; 82(3): 118.

No abstract available.

Emerging health benefits of CLA (conjugated linoleic acid).

McBean, L.D.

Dairy Council Digest 1999. Rosement, IL: National Dairy Council.

No abstract available.

Cyclical breast pain--some observations and the difficulties in treatment.

McFayden IJ, Forrest AP, Chetty U, Raab G. Longmore Breast Unit, Western General Hospital, Edinburgh.

Br J Clin Pract 1992 Autumn;46(3):161-4

This paper describes a retrospective study of the clinical aspects and treatment of 566 women with cyclical breast pain over a seven-year period. Figures for the effectiveness of simple treatments including some homeopathic drugs are reported. The article concludes that reassurance is the fundamental treatment. Good responses are obtained from simple and safe drugs (oil of evening primrose, vitamin B6) with minimal side-effects. The use of stronger hormone drugs such as tamoxifen and danazol was only necessary in a small proportion of patients and resulted in a higher incidence of side-effects.

Danazol increases the anticoagulant effect of warfarin.

Meeks ML; Mahaffey KW; Katz MD Department of Pharmacy Services, University of Arizona Health Sciences Center, Tucson.

Ann Pharmacother (UNITED STATES) May 1992, 26 (5) p641-2

OBJECTIVE: To report two cases demonstrating an interaction between danazol and warfarin, resulting in the potentiation of warfarin's effect and bleeding complications. DATA SOURCES: Case reports, review articles, and studies identified by MEDLINE. STUDY SELECTION: All published English-language reports involving danazol and warfarin interactions were reviewed. DATA SYNTHESIS: Danazol, a synthetic testosterone derivative, is used in the treatment of endometriosis, fibrocystic breast disease , menorrhagia protein C deficiency, and hemophilia. We describe two cases including an interaction between danazol and warfarin, resulting in bleeding complications. There are at least two other reported cases of this interaction. This interaction may be attributable to several mechanisms. Danazol may inhibit the metabolism of warfarin and/or it may have a direct effect on the coagulation and fibrinolytic systems. CONCLUSIONS: Based on this report and other published cases, clinicians must be aware that danazol may increase the anticoagulant effect of warfarin. Patients receiving warfarin who are prescribed danazol must be monitored closely to prevent excessive anticoagulation and subsequent bleeding. Studies are needed to determine the frequency of this interaction and its underlying mechanisms.

Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells.

Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Department of Radiation Oncology and. Department of Otolaryngology, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA.

J Nutr 2000 Dec;130(12):2927-31

Estrogen, via its binding to the estrogen receptor (ER), plays an important role in breast cancer cell proliferation and tumor development. Indole-3-carbinol (I3C), a compound occurring naturally in cruciferous vegetables, exhibits a potent antitumor activity via its regulation of estrogen activity and metabolism. This study was designed to determine the effect of I3C on the potential to inhibit the ER-alpha. Using a reporter gene driven by the estrogen receptor, I3C (10-125 micromol/L) significantly repressed the 17ss-estradiol (E2)-activated ER-alpha signaling in a dose-dependent manner. I3C and breast cancer susceptibility gene 1 (BRCA1) synergistically inhibited transcriptional activity of ER-alpha. Moreover, I3C down-regulated the expression of the estrogen-responsive genes, pS2 and cathepsin-D, and up-regulated BRCA1. The inhibitory effects of I3C did not contribute to its cytotoxic effects because these activities were observed at less than toxic concentrations. These results further suggest that antitumor activities of I3C are associated not only with its regulation of estrogen activity and metabolism, but also its modulation of ER transcription activity.

Vitamin E and benign breast disease.

Meyer EC, Sommers DK, Reitz CJ, Mentis H. Department of Pharmacology, University of Pretoria, South Africa.

Surgery 1990 May;107(5):549-51

Vitamin E has been used in the treatment of benign breast disease for 25 years. To evaluate the efficacy of treatment by means of mammography as the objective and sensitive parameter, 105 women were randomly selected and entered into a double-blind, placebo-controlled crossover trial. All patients had mammographic evidence of benign breast disease. They received 600 mg of placebo and alpha-tocopherol acetate in 3-month treatment phases. Breast examinations and mammography were done, after each treatment, at approximately the same phase of the patients menstrual cycle. No significant subjective or objective effects after treatment were observed. We conclude that alpha-tocopherol is not beneficial in the treatment of benign breast disease. We would warn against the use of alpha-tocopherol for misdirected treatment of undiagnosed overt disease because such treatment may delay the diagnosis of breast cancer.

Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.

Michnovicz JJ, Adlercreutz H, Bradlow HL. Rockefeller University Hospital and The Institute for Hormone Research, New York, NY 10016, USA.

J Natl Cancer Inst 1997 May 21;89(10):718-23

BACKGROUND: The oxidative metabolism of estrogens in humans is mediated primarily by cytochrome P450, many isoenzymes of which are inducible by dietary and pharmacologic agents. One major pathway, 2-hydroxylation, is induced by dietary indole-3-carbinol (I3C), which is present in cruciferous vegetables (e.g., cabbage and broccoli).

PURPOSE: Because the pool of available estrogen substrates for all pathways is limited, we hypothesized that increased 2-hydroxylation of estrogens would lead to decreased activity in competing metabolic pathways.

METHODS: Urine samples were collected from subjects before and after oral ingestion of I3C (6-7 mg/kg per day). In the first study, seven men received I3C for 1 week; in the second study, 10 women received I3C for 2 months. A profile of 13 estrogens was measured in each sample by gas chromatography-mass spectrometry.

RESULTS: In both men and women, I3C significantly increased the urinary excretion of C-2 estrogens. The urinary concentrations of nearly all other estrogen metabolites, including levels of estradiol, estrone, estriol, and 16alpha-hydroxyestrone, were lower after I3C treatment.

CONCLUSIONS: These findings support the hypothesis that I3C-induced estrogen 2-hydroxylation results in decreased concentrations of several metabolites known to activate the estrogen receptor. This effect may lower estrogenic stimulation in women.

IMPLICATIONS: I3C may have chemopreventive activity against breast cancer in humans, although the long-term effects of higher catechol estrogen levels in women require further investigation.

Nonendocrine theories of the etiology of benign breast disease.

Minton JP, Abou-Issa H.

World J Surg 1989 Nov-Dec;13(6):680-4

This article summarizes 15 years of clinical and laboratory studies that have continued the search for a biochemical basis for the development and resolution of symptomatic benign fibrocystic disease. The clinical response to diet modifications is presented along with simultaneous laboratory tissue and serum studies. An ongoing study of the clinical response to complete and total methylxanthine abstention, especially caffeine, is presented in the initial part of the article. Following the clinical observations, is a series of laboratory studies, some of which actually preceded the clinical investigation and, in fact, pointed out that a beneficial clinical response might occur in some women following complete abstention. In the last paragraph, we present current information that may identify which women are susceptible to fibrocystic breast disease development.

Clinical and biochemical studies on methylxanthine-related fibrocystic breast disease.

Minton JP, Abou-Issa H, Reiches N, Roseman JM.

Surgery 1981 Aug;90(2):299-304

The results of this study show that the consumption of methylxanthines through dietary sources appears to be associated with the etiologic development of benign fibrocystic disease in the American woman. Complete abstention from methylxanthine consumption resulted in complete resolution of the disease in 82.5% and significant improvement in 15% of those studied. Thus 97.5% showed clinical benefit from total methylxanthine abstention. The results of a clinical questionnaire answered by 500 women consuming ethylxanthines, one half of whom had fibrocystic breast disease, suggest that women with fibrocystic disease may have a genetic predisposition for both benign breast disease and cancer. Biochemical studies implicate increased sensitivity of the adenylate cyclase system to catecholamines in patients with fibrocystic disease. Methylxanthines are known to increase circulating catecholamines.

Caffeine, cyclic nucleotides, and breast disease.

Minton JP, Foecking MK, Webster DJ, Matthews RH.

Surgery 1979 Jul;86(1):105-9

Methylxanthine consumption is associated with the development of fibrocystic disease of the breast. Methylxanthine abstention is associated with resolution of signs and symptoms of fibrocystic disease. Abstinence from methylxanthine consumption decreased breast biopsies and the need for major breast surgery because of benign disease. Methylxanthine consumption is associated with elevated cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) values in fibrocystic dsiease over those obtained in normal breast tissue.

Noncontraceptive benefits of oral contraceptives.

Mishell DR Jr. Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles 90033.

J Reprod Med 1993 Dec;38(12 Suppl):1021-9

The noncontraceptive health benefits of oral contraceptives were initially summarized a decade ago. Studies conducted in the last decade confirmed the findings of earlier studies with high-dose oral contraceptives and extended them to low-dose formulations. Among the noncontraceptive health benefits first cited were reductions in menorrhagia, irregular menses, endometrial cancer, ovarian cancer, functional ovarian cysts, benign breast disease, dysmenorrhea, premenstrual tension and iron-deficiency anemia. In addition, women who used oral contraceptives were less likely to develop rheumatoid arthritis or acute salpingitis, particularly moderate or severe forms, than were women using no method of contraception. Despite the fact that such benefits were identified more than 10 years ago and despite their inclusion in oral contraceptive labeling, women today are largely unaware of the noncontraceptive health benefits associated with oral contraceptive use.

Efficacy of low fat diet in the treatment of benign breast disease.

Mishra SK, Sharma AK, Salila M, Srivastava AK, Bal S, Ramesh V. Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, India.

Natl Med J India 1994 Mar-Apr;7(2):60-2

BACKGROUND. Previous studies have shown that lipid abnormalities have a role in the pathogenesis of benign breast disease. However, few investigators have tried to reduce dietary fat to treat this disorder.

METHODS. Between 1990 and 1993, we conducted a prospective cohort study to find out the efficacy of a low fat diet (less than 15% fat-derived calories) in the treatment of benign breast disease in patients who had been symptomatic for 6 months or more. The study was conducted in two phases. In the first phase 36 patients were alternately assigned to control and treatment groups for 6 months and in the second phase 121 patients (including all those in phase I) were given treatment (median follow up 25 months, range 3 to 39 months). Detailed lipid profiles were studied at the time of presentation and at 4 and 5 months.

RESULTS. Phase I results showed that after 6 months none of the patients in the control group had experienced any alteration in their symptoms and signs but in the treatment group 12 out of 17 improved. In phase II improvement in pain (68 out of 97; 70%), nodularity (51 out of 79; 64%) and discharge (15 out of 19; 80%) was seen. There was a significant decline in the mean values of total cholesterol and high-density lipoproteins at the end of 5 months of treatment.

CONCLUSION. A low fat diet improves the symptoms as well as the lipid profile in patients with benign breast disease.

In vitro hormonal effects of soybean isoflavones.

Molteni A, Brizio-Molteni L, Persky V. Department of Pathology, Northwestern University, Chicago, IL.

J Nutr 1995 Mar;125(3 Suppl):751S-756S

Isoflavones exhibit a multitude of biological effects that influence cell growth and regulation, and, thus, may have potential value in the prevention and treatment of cancer. Isoflavones are weak estrogens and can function both as estrogen agonists and antagonists depending on the hormonal milieu and the target tissue and species under investigation. Genistein, one of the two primary isoflavones in soybeans, has attracted much attention from the research community, not only because of its potential antiestrogenic effects, but because it inhibits several key enzymes thought to be involved in carcinogenesis. Although still speculative, greater dietary incorporation of soybean products, because of the high concentration of isoflavones, may be a safe and effective means of reducing cancer risk.

Gourmet treats to keep you healthy.

Mowatt, T.

Life Extension Magazine 1998 Jun; 4(6): 22-6.

Ft. Lauderdale, FL: Life Extension Foundation.

Hippocampal perfusion and pituitary-adrenal axis in Alzheimer's disease.

Murialdo G, Nobili F, Rollero A, Gianelli MV, Copello F, Rodriguez G, Polleri A. Department of Endocrinological and Metabolic Sciences, Epidemiology Service, University of Genova, Italy. disem@unige.it

Neuropsychobiology 2000;42(2):51-7

The hippocampus is involved in Alzheimer's disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate beta-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion - evaluated by SPECT - and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by (99m)Tc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia. Copyright 2000 S. Karger AG, Basel.

Benign Breast Lumps and Other Benign Breast Changes 2001a.

National Cancer Institute.

Bethesda, MD (http://rex.nci.nih.gov).

Understanding Breast Changes. About Breast Lumps and Other Changes 2001b.

National Cancer Institute.

Bethesda, MD (http://cancernet.nci.nih.gov).

Benign Breast Disease: Summary of Risk Factors for Breast Cancer

NBCC.

1999 Jul 15. Campersdown, NSW, Australia:

National Breast Cancer Centre.

Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men.

Nestler JE, Barlascini CO, Clore JN, Blackard WG. Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.

J Clin Endocrinol Metab 1988 Jan;66(1):57-61

To assess the effects of dehydroepiandrosterone (DHEA) on body fat mass, serum lipid levels, and tissue sensitivity to insulin, five normal men were given placebo and five normal men were given oral DHEA [1600 mg/day (554.7 mmol/day)] for 28 days in a randomized, double blind study. In the DHEA group serum DHEA-S levels rose 2.5- to 3.5-fold, and mean ( SEM) serum androstenedione rose from 4.3 0.6 to 8.6 1.2 nmol/L (P less than 0.004, by paired t test), but serum total testosterone, free testosterone, sex hormone-binding globulin, estradiol, and estrone levels did not change. In the DHEA group the mean percent body fat decreased by 31%, with no change in weight. This suggests that the reduction in fat mass was coupled with an increase in muscle mass. DHEA administration also resulted in a fall in mean serum total cholesterol concentration (4.82 0.21 vs. 4.48 0.29 nmol/L; P less than 0.05), which was due almost entirely to a fall of 7.5% in mean serum low density lipoprotein cholesterol (3.21 0.11 vs. 2.97 0.14 nmol/L; P less than 0.01). No changes in anthropometric parameters or serum lipid levels occurred in the placebo group. Tissue sensitivity to insulin, assessed by the hyperinsulinemic-euglycemic clamp technique, did not change in either the placebo or DHEA groups. These results suggest that in normal men DHEA administration reduces body fat, increases muscle mass, and reduces serum low density lipoprotein cholesterol levels. Tissue sensitivity to insulin was unaffected by short term DHEA administration.

Background Information. Indole-3-Carbinol (I3C), 700-06-1

NIEHS.

June 2000. Research Triangle Park, NC: National Institute of Environmental Health Sciences

(http://ntp-server.nih.gov/htdocs/Chem_Background/ExecSumm/Indolecarbinol.html).

Environmental estrogenic effects of alkylphenol ethoxylates.

Nimrod AC, Benson WH. Department of Pharmacology and Environmental Toxicology Research Program/RIPS School of Pharmacy, University of Mississippi, University 38677, USA.

Crit Rev Toxicol 1996 May;26(3):335-64

Alkylphenol ethoxylates (APEs) and related compounds recently have been reported to be estrogenic because it has been demonstrated in laboratory studies that they mimic the effects of estradiol both in vitro and in vivo. Chemicals referred to as "environmental estrogens" are suspected of causing health effects in both humans and wildlife through disruption of the endocrine system. In this review, the occurrence, environmental fate, and biological effects of APEs are presented. To provide understanding of the potential for endocrine disruption due to environmental estrogens, the physiology of estrogens in mammals and fish is also reviewed. The estrogenic potency of other environmental estrogens is compared to the potency of APE degradation products. The reproductive effects of estrogenic compounds are considered when evaluating the potential health effects of APEs. Given the reported environmental concentrations and bioconcentration factors of APE products, the potential for these compounds to produce estrogenic effects in the environment appears low. Although questions concerning the physiological effects of APEs and other environmental estrogens remain unanswered, there are indications that research is in progress that will lead to better understanding of the risks to humans and wildlife.

Benign breast pain in women: a practical approach to evaluation and treatment.

Norlock FE. Cook County Hospital, USA.

J Am Med Womens Assoc 2002 Spring;57(2):85-90

The literature on breast pain etiology, practical approaches to evaluating benign breast pain, and effective treatments was reviewed. Medline, the Cochrane Database of Systematic Reviews, and Cancerlit were searched for 1975 to 2001. Researchers have found no clear hormonal or specific pathological processes that explain cyclical breast pain. Some investigations did find associations between breast pain and premenstrual syndrome, fibrocystic breast disease, and caffeine intake. Initial treatment with reassurance, a well-fitted brassiere, caffeine reduction, and primrose oil should be tried before prescribing pharmaceutical agents. Medications such as danazol, bromocriptine, and tamoxifen are effective, but often have side effects and contraindications. Future studies should indude double-blind, randomized, controlled trials of selective-serotonin reuptake inhibitors and primrose oil and single-blind, randomized, controlled trials advising caffeine reduction.

Breast biopsy for mammographically detected non-palpable lesions using a vacuum-assisted biopsy device (Mammotome) and an upright-type stereotactic mammography unit.

Ohsumi S, Takashima S, Aogi K, Ishizaki M, Mandai K. Department of Surgery, National Shikoku Cancer Center, 13 Hori-no-uchi, Matsuyama, Ehime 790-0007, Japan. sosumi@shikoku-cc.go.jp

Jpn J Clin Oncol 2001 Nov;31(11):527-31

BACKGROUND: It is planned to start screening mammography throughout Japan in the near future. However, a minimally invasive biopsy procedure for mammographically detected non-palpable breast lesions is not available in almost all Japanese hospitals. It is crucial to develop a useful minimally invasive biopsy method which can be applied without difficulty. METHODS: Eighty-nine biopsies for 88 mammographically detected non-palpable breast lesions, consisting of 70 lesions with microcalcifications alone, eight masses without calcifications and 10 with both masses and microcalcifications, were performed using the combination of a vacuum-assisted biopsy device (Mammotome) and an upright-type stereotactic mammography unit. RESULTS: Microcalcifications were confirmed radiographically in the tissue obtained from 78 biopsies among 81 biopsies for the lesions with microcalcifications (96.3%). All the lesions without calcifications were considered to be biopsied successfully. Five patients complained of nausea or fainted during the localization or biopsy procedure and an additional patient suffered from hyperventilation syndrome. Five cases experienced mild subcutaneous bleeding in the breasts. CONCLUSIONS: The biopsy technique using the combination of a vacuum-assisted biopsy device and an upright-type stereotactic mammography unit is a cost-effective, safe and very useful method for mammographically detected non-palpable breast lesions. It is expected to be a standard method of biopsy for such lesions in many developed countries other than the USA. However, it is important to make the patients relaxed during the biopsy to prevent mental strain.

Mammographic parenchymal patterns: a marker of breast cancer risk.

Oza AM, Boyd NF. Department of Medicine, Princess Margaret Hospital and Ontario Cancer Institute, Toronto, Canada.

Epidemiol Rev. 1993;15(1):196-208.

There is now a large amount of evidence showing that mammographic densities are an indicator of increased risk of breast cancer. There is as yet no generally agreed upon and recognized method of classifying these densities, although the available evidence shows that quantitative description of densities creates larger gradients of risk than Wolfe's classification and larger risk gradients than most other risk factors for breast cancer. It seems likely that improved methods of describing densities quantitatively, and possibly other methods of characterizing the tissue changes that are responsible for the densities, will allow greater discrimination. However, it is already clear that breast cancer develops in a large number of women who do not have radiologic changes indicating increased risk, and that it is unlikely that mammographic pattern, or any other risk factor for breast cancer identified to date, will be useful for the selection of women for mammographic screening. Although mammographic densities are associated with an increased risk of developing histologic changes that are risk factors for breast cancer, the histologic feature most consistently associated with mammographic densities is stromal fibrosis. We suggest that the relation between stromal fibrosis and risk of breast cancer can be explained by the known actions of a variety of growth factors that are thought to play a role in a number of aspects of breast development and carcinogenesis. The association between mammographic densities and several other risk factors for breast cancer suggests that these factors may also modulate the activity of growth factors in breast tissue, and that this may be the means by which they influence breast cancer risk. Further research is needed to determine whether differences in the activity of growth factors in breast tissue can be found in association with radiologic and other risk factors for breast cancer. The available evidence indicates, therefore, that mammographic parenchymal patterns do, at least in part, meet the criteria outlined in the introduction of this paper. Some mammographic appearances are associated with a substantial increase in the risk of breast cancer, and, as shown by observations on the effects of hormone use, are capable of change. Mammographic densities have also been found to be associated with biochemical characteristics of possible relevance to carcinogenesis. The appearances that are related to risk may, therefore, be most useful as a means of investigating the etiology of breast cancer and of testing hypotheses about potential preventive strategies.

Mammographic and ultrasonographic study of changes in the breast related to HRT.

Ozdemir A, Konus O, Nas T, Erbas G, Cosar S, Isik S. Department of Radiology, University of Gazi, School of Medicine, Besevler, Ankara, Turkey. aozdemir@med.gazi.edu.tr

Int J Gynaecol Obstet 1999 Oct;67(1):23-32

OBJECTIVE: To determine the frequency and degree of change in mammographic densities, and new solid or cystic formations in the breast tissue, during different types of hormone replacement therapy (HRT).

SUBJECTS AND METHODS: This prospective study included 118 postmenopausal women, 88 under hormone replacement therapy and 30 control subjects. Four types of hormone therapies were compared for their effects on mammograms and sonograms obtained before and during therapy. Mean duration of follow-up was 16.92 7.65 months in the treated and 21.56 11.49 months in the control group. Density changes on mammograms were evaluated subjectively.

RESULTS: Density increase was recorded in 34% of the patients receiving HRT and in none of the control subjects (P &lt; 0.01). Highest frequency of density increase was found in the groups treated with estrogen plus cyproterone acetate (46%) and with estrogen plus medroxyprogesterone acetate (43%). Frequencies of density increase in the tibolone users, and in estrogen alone users were 28% and 18%, respectively. Degree of density increase was evidently minimal in tibolone users, compared to others. New cysts occurred in six patients receiving HRT (6%) which was not statistically different from the control group (16%) (P &gt; 0.05). New cyst formation was not related to the degree of density increase. New solid mass formation was not observed.

CONCLUSION: Our findings show that mammographic density changes related to HRT are dependent on the selected hormone regimen. Formations of breast cysts or solid lesions do not seem to be related to HRT.

Management of cyclical mastalgia.

Pain JA, Cahill CJ. King's College Hospital, London.

Br J Clin Pract 1990 Nov;44(11):454-6

In order to establish the current treatment of cyclical mastalgia, a postal questionnaire was sent to 276 consultant general surgeons (over 25% of the UK total), randomly selected from the 12 UK regional health authorities. Surgeons were questioned about their choices of treatment for cyclical mastalgia, after initial resassurance, and for persistent pain. Two hundred and forty-five (89%) responded, out of whom 219 saw patients with breast disease. Twenty-three (11%) of these surgeons were identified as having a major interest in breast disease. Danazol, used by 75% of surgeons, was the drug most commonly prescribed. Initial treatments by non-specialist surgeons included danazol (31%), analgesia (19%) and diuretics (17%), and by breast surgeons evening primrose oil (30%), tamoxifen (13%) and vitamin B6 (13%). For persistent pain 46% of non-specialist surgeons prescribed danazol and 18% surgery, whereas 65% of breast surgeons prescribed danazol and 30% bromocriptine. A wide variety of therapies are used, but danazol is the most common. For persistent unresponsive pain, local excision biopsy surgery is frequently considered by non-specialist surgeons. Breast specialist tend initially to use other methods that are associated with fewer side-effects and reserve other treatments such as danazol and bromocriptine for persistent cases.

Estrogen replacement therapy and fibrocystic breast disease.

Pastides H, Najjar MA, Kelsey JL. Division of Public Health, University of Massachusetts School of Health Sciences, Amherst 01003.

Am J Prev Med 1987 Sep-Oct;3(5):282-6

In a hospital-based case-control study conducted in New Haven, Connecticut, women experiencing estrogen replacement therapy were found to be at twice the risk of nonusers for histologically confirmed fibrocystic breast disease (odds ratio = 2; 95 percent confidence limits = 1-3.9) if their menopause was natural. No excess risk was found for women experiencing a surgical menopause. The highest risk for fibrocystic disease was observed for women with more than three years of estrogen replacement therapy. When therapy occurred was not significantly related to the risk of disease once duration of use was controlled for. These results suggest an etiologic role of estrogen replacement therapy in the development or promotion of fibrocystic breast disease.

Female pseudohermaphroditism with somatic chromosomal anomaly in association with in utero exposure to danazol

Peress M.R.; Kreutner A.K.; Mathur R.S.; Williamson H.O. Sect. Reprod. Endocrinol. Infertil., Dept. Obstet. Gynecol., Med. Univ. South Carolina, Charleston, SC 29425 United States

American Journal of Obstetrics and Gynecology 1982, 142/6 I (708-709)

Female pseudohermaphroditism is characterized by XX karyotype, female internal reproductive organs, but ambiguous external genitals, usually as a result of in utero exposure to excess androgens. Such androgens may be of exogenous, fetal, or maternal origin. Congenital adrenal hyperplasia (CAH) with excessive fetal androgen production is the most common underlying disorder causing female pseudohermaphroditism. Masculinization of the female fetus as a result of increased maternal androgen production is rare but has been reported with luteoma of pregnancy and arrhenoblastoma. Female pseudohermaphroditism has also been reported after prenatal exposure to synthetic progestogens, stilbestrol, and prenatal vitamins containing methyltestosterone. Williamson reported a female pseudohermaphrodite with CAH and incidental in utero exposure to medroxyprogesterone acetate. More recently, Duck and associates reported the association of female pseudohermaphroditism with in utero exposure to danazol. This compound has been used in the treatment of endometriosis, fibrocystic breast disease , precocious puberty, dysfunctional uterine bleeding, and angioneurotic edema.

MR-Guided vacuum biopsy of 206 contrast-enhancing breast lesions.

Perlet C, Schneider P, Amaya B, Grosse A, Sittek H, Reiser MF, Heywang-Kobrunner SH. Institut fur Klinische Radiologie, Klinikum der Universitat Grosshadern, Munchen.

Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2002 Jan;174(1):88-95

Abstract. PURPOSE: To detemine the accuracy and clinical use of MR-guided vacuum biopsy (VB) of enhancing breast lesions. MATERIAL AND METHODS: 254 lesions were referred to MR-guided vacuum-assisted breast biopsy. In 43 (16 %) patients the indication was dropped because the lesions could not be identified at the time VB was scheduled. This was due to hormonal influences (n = 37), to too strong compression (n = 3) or to misinterpretation of the initial diagnostic MRI (n = 3). In 5 cases (2 %) VB was not performed due to obesity (n = 2); problems of access (n = 2) or a defect of the MR-unit (n = 1). VB was performed on altogether 206 lesions. In 4 cases (2 %) VB was unsuccessful. This was immediately realized on the post-interventional images. Thus a false negative diagnosis was avoided. Verification included excision of the cavity in cases with proven malignancy or atypical ductal hyperplasia (ADH) and (for benign lesions) retrospective correlation of VB-histology with pre-and postinterventional MRI and subsequent follow-up. RESULTS: 51/202 successful biopsies proved malignancy. In 7 cases ADH and in 144 cases a benign lesion was diagnosed. One DCIS was underestimated as ADH. All other benign or malignant diagnoses proved to be correct. CONCLUSION: MR-guided VB allows reliable histological work-up of contrast-enhancing small lesions which are not visible by any other modality.

Dementia: a neuroendocrine perspective.

Polleri A, Gianelli MV, Murialdo G. Department of Endocrinological and Metabolic Sciences, University of Genoa, Italy.

J Endocrinol Invest 2002 Jan;25(1):73-83

The etiology of Alzheimer's disease (AD) has not been as yet completely defined. Genetic, environmental and neurophysiological aspects should all be taken into account. The disease has also neuroendocrine implications, some of which are discussed in this review. It is known that stress and glucocorticoids may affect neurone survival. On the contrary, some data indicate that DHEA and DHEAS exert a neuroprotective action. In AD, changes in hypothalamic-pituitary-adrenal axis function have been reported. Experimental and clinical evidence indicates that glucocorticoid hypersecretion and DHEAS levels decrement may add to hippocampal dysfunction in aging and in AD. Glucocorticoid and beta-amyloid concur in the mechanism of neurone damage, as well as excitatory amino acids (EAA), Ca++ and reactive oxygen species (ROS). The neuroprotective effects exerted by IGFs are also hindered in aging and even more in AD. Production and biological actions of IGFs are negatively influenced by cortisol hypersecretion and DHEAS decrease in patients with AD.

Clinical experience of drug treatments for mastalgia.

Pye JK, Mansel RE, Hughes LE.

Lancet 1985 Aug 17;2(8451):373-7

Results of randomised trials and open studies in 291 patients with severe persistent breast pain in whom breast cancer had been excluded showed that drug therapy produced a good or useful result in 77% of those with cyclical mastalgia and 44% of those with non-cyclical mastalgia. In patients with cyclical mastalgia good or useful responses were obtained with danazol in 70%, with bromocriptine in 47%, and with evening-primrose oil in 45%. The equivalent response rates in patients with non-cyclical mastalgia were 31%, 20%, and 27% respectively. Progestagens were not effective in either group. Failure to respond to one drug did not preclude response to a different drug. Patients with Tietze's syndrome did not respond to drug therapy, but 7 out of 10 responded to injection of lignocaine and hydrocortisone around the affected costochondral junction.

Complex carbohydrates: they're the best thing since sliced bread.

Quagliani, D.

Better Homes &amp;amp; Gardens 1997 May.

No abstract available.

A cohort study of oral contraceptive use and risk of benign breast disease.

Rohan TE, Miller AB. Department of Public Health Sciences, University of Toronto, Canada. tom.rohan@utoronto.ca

Int J Cancer 1999 Jul 19;82(2):191-6

The purpose of the cohort study reported here was to investigate the association between oral contraceptive use and risk of benign breast disease (BBD), overall and by histological subtype, within the 56,537 women in the Canadian National Breast Screening Study (NBSS) who completed self-administered lifestyle and dietary questionnaires. The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment. Cases were the 2,116 women in the dietary cohort who were diagnosed with biopsy-confirmed incident BBD. For comparative purposes, a subcohort consisting of a random sample of 5,681 women (including 197 subjects with incident BBD) was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 2,116 cases and 5,338 non-cases. There was an inverse association between use of oral contraceptives and risk of all types of BBD combined. The reduction in risk was confined largely to proliferative forms of BBD (BPED), and in particular, to those forms of BPED without histological atypia, in whom there was a progressive reduction in risk with increasing duration of use (the IRR (95% CI) for use of more than 7 years was 0.64 (0.47-0.87)); risk of BPED with atypia was increased somewhat in association with oral contraceptive use (the IRR (95% CI) for use of more than 7 years was 1.43 (0.68-3.01 )), but not in a dose-dependent manner. The results were similar when examined separately in the screened and control arms of the NBSS and for screen-detected and interval-detected BPED.

Why grass makes for better milk.

Roloff, J.

Science News 1997 Oct 11.

No abstract available.

Effect of a low-fat diet on hormone levels in women with cystic breast disease. I. Serum steroids and gonadotropins.

Rose DP, Boyar AP, Cohen C, Strong LE.

J Natl Cancer Inst 1987 Apr;78(4):623-6

For examination of the effect of a low-fat diet on serum estrogen, progesterone, and gonadotropin levels, 16 patients with cystic breast disease and cyclic mastalgia were studied before dietary intervention and at 2 and 3 months thereafter. Four-day food diaries indicated that total fat intake was reduced from a prediet average of 69 g (35% of total kilocalories/day) to an average of 32 g (21% of total kilocalories) after 3 months. Highly significant reductions (P less than .001) occurred in dietary cholesterol and less changes occurred in protein and total kilocalorie consumption (P less than .05); fiber intakes were not affected. After 3 months on this low-fat diet, there were significant reductions in luteal-phase serum total estrogens (P less than .001), estrone (P less than .005), and estradiol (P less than .01); progesterone, luteinizing hormone, and follicle-stimulating hormone levels were unchanged. Two of the 16 patients were excluded from the hormone statistical analyses because the serum progesterone levels were not consistent with sampling in the luteal phase of the menstrual cycle. It is concluded that a reduction of dietary fat intake to 20% of the total kilocalories will result in significant decreases in circulating estrogens in benign breast disease patients and that this effect is achievable without increasing dietary fiber consumption. Absence of changes in serum progesterone and gonadotropins during the dietary intervention is consistent with altered enterohepatic circulation of estrogens rather than with effects on the pituitary-ovarian axis.

Effect of a low-fat diet on hormone levels in women with cystic breast disease. II. Serum radioimmunoassayable prolactin and growth hormone and bioactive lactogenic hormones.

Rose DP, Cohen LA, Berke B, Boyar AP.

J Natl Cancer Inst 1987 Apr;78(4):627-31

For investigation of the bioactivity of circulating prolactin and growth hormone (lactogenic hormones) in symptomatic benign breast disease, serum was assayed by the Nb2 lymphoma cell method in premenopausal patients with cystic breast disease and cyclic mastalgia and in normal premenopausal women. The results were compared with serum prolactin and growth hormone concentrations determined by radioimmunoassay. The serum bioassayable hormone levels in the benign breast disease patients (74.0 77.6 ng/ml) were significantly higher (P less than .001) than in normal women (23.8 10.7 ng/ml). There were no significant differences in the radioimmunoassayable prolactin or growth hormone levels between the 2 groups. When 16 cystic breast disease patients were placed on a low-fat (20% of total kilocalories) diet for 3 months, there were significant reductions in the serum bioassayable hormone levels (P less than .02). It is concluded that the bioactivity of prolactin may be elevated in the serum of patients with cystic breast disease and cyclic mastalgia, without corresponding increases in levels determined by radioimmunoassay; that this abnormality is reversible by a reduction in dietary fat consumption to 20% of the total kilocalories; and that serum prolactin may provide a valuable biomarker in clinical trials of a low-fat diet in women at high breast cancer risk.

Breast cancer and the consumption of coffee.

Rosenberg L, Miller DR, Helmrich SP, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S.

Am J Epidemiol 1985 Sep;122(3):391-9

The hypothesis has been raised that coffee consumption may increase the incidence of breast cancer, based on the report that fibrocystic breast disease, a risk factor for breast cancer, regresses after abstention from coffee and other methylxanthines. The relation between recent coffee consumption and the risk of breast cancer was evaluated in a case-control study, based on interviews conducted 1975-1982 at several mainly eastern US teaching and community hospitals. The responses of 2,651 women with newly diagnosed breast cancer were compared with those of 1,501 controls with nonmalignant conditions and 385 controls with cancers at other sites. The relative risk estimates for levels of coffee drinking up to seven or more cups daily, relative to none, approximated 1.0 with narrow 95% confidence intervals. After allowance for confounding, the relative risk estimate for drinking at least five cups a day was 1.2 (95% confidence interval, 0.9-1.6) using the noncancer controls and 1.1 (0.7-1.6) using the cancer controls. Coffee consumption was not associated with an increase in the risk of breast cancer among women with a history of fibrocystic breast disease, nor were tea or decaffeinated coffee associated with an increase in the risk of breast cancer. The results suggest that the recent consumption of coffee does not influence the incidence of breast cancer.

Caffeine restriction as initial treatment for breast pain.

Russell LC. Department of Surgery, Duke University Medical Center, Durham, N.C.

Nurse Pract 1989 Feb;14(2):36-7, 40

The effects of methylxanthines (caffeine, theophylline and theobromine) on the symptoms associated with fibrocystic breast disease were studied in 147 patients. Disease was documented by mammography, physical examination and clinical symptoms. Only those individuals with breast pain (n = 138) were included in the study. Questionnaires were presented and explained to all patients by the same nurse examiner. Patients reported their degree of caffeine consumption as either light (two cups per day or less of caffeine-containing beverages or foods), moderate (more than two cups, but less than six cups per day), or heavy (six cups per day or more of caffeine-containing products). They additionally reported breast pain as mild, moderate or severe. Past medical and family histories were reported as well as medication intake. All patients were counseled to abstain from or reduce caffeine consumption and were given a list of commonly used caffeine-containing products. The results at the end of one year indicated that compliance was high, with 113 patients (81.9 percent) reducing their caffeine intake substantially and, of those, 69 (61 percent) reporting a decrease or absence of breast pain. This study supports the findings of others in that caffeine restriction is an effective means of management of breast pain associated with fibrocystic disease.

The use of silymarin in the treatment of liver diseases.

Saller R, Meier R, Brignoli R. Abteilung Naturheilkunde, University Hospital Zurich, Switzerland.

Drugs 2001;61(14):2035-63

The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p &lt; 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p &lt; 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p &lt; 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.

Beta-carotene supplementation associated with intermittent retinol administration in the treatment of premenopausal mastodynia.

Santamaria L, Dell'Orti M, Bianchi Santamaria A.

Boll Chim Farm 1989 Sep;128(9):284-7

Twenty-five women, 23-41 year old, suffering from premestrual cyclical mastodynia linked or otherwise to benign breast disease (BBD), with moderate or severe pain at least seven days before each menstrual period, were treated with daily beta-carotene (BC) supplementation associated with intermittent administration of retinol (all-trans-retinol 300,000 IU per day). In this therapy retinol was given for 7 days immediately before each menstrual period. After 6 months' treatment, the results revealed marked reduction in breast pain, and sometime recovery, in 23-41 year old women with no toxic side effects. But no such advantages in 5 women with non-cyclical mastodynia treated as above were found. Above this age range, the advantages appear to be absent. All the women developed a healthy look because of a slight tanning of the skin due to beta-carotene supplementation. These data demonstrated a therapeutic synergism between BC and retinol.

Methylxanthines and benign breast disease.

Schairer C, Brinton LA, Hoover RN.

Am J Epidemiol 1986 Oct;124(4):603-11

The relation between methylxanthine consumption and biopsied benign breast disease was investigated by using data from a case-control study which included 1,569 cases and 1,846 controls identified between 1973 and 1980 through a nationwide screening program. There was no evidence of an association between methylxanthine consumption and benign breast disease in the total study population. When histologic types of benign breast disease were examined, there were no trends in risk according to methylxanthine consumption among the 813 cases with fibrocystic disease, the 508 cases for whom detailed pathology data were not available, the 172 cases with benign neoplasms, or the 156 cases with other benign conditions. When cases with fibrocystic disease were examined according to presence of atypia, hyperplasia, sclerosing adenosis, or cysts, there was, again, no association between methylxanthine consumption and risk of disease. In addition, no relation was found between methylxanthine consumption and menstrual breast tenderness among premenopausal women with fibrocystic disease or unknown conditions.

Oral contraceptives in the 90s.

Scott, P.M.

Physician Assist. 1993; 17(12): 19-28.

No abstract available.

Adipose tissue as a source of hormones.

Siiteri PK.

Am J Clin Nutr 1987 Jan;45(1 Suppl):277-82

Obesity is known to increase the risk for cancer of the reproductive tract in women. The mechanism underlying this association can be explained by increased estrogenic stimulus to estrogen-target tissues as the result of three factors. First, increased adrenal secretory activity makes more androgen precursors available for conversion to estrogen in peripheral tissues. Second, the efficiency of conversion of androstenedione (A) to estrone (E1), is elevated in obese subjects because adipose tissue is the major tissue site of conversion. Third, plasma levels of SHBG, which binds estradiol (E2), are depressed in obese subjects and greater than normal amounts of serum estradiol are therefore available to target tissues from the circulation. Recent studies have shown that the levels of estrogens and other steroid hormones in breast fluids are much higher than in serum, which may be the result of local synthesis or increased uptake from the circulation. No differences in estrogen levels of breast fluid have been found between normal women and those with breast disease. A possible explanation may be differences in the levels of estrogen antagonists, such as progesterone.

Aromatization of androgens in women: current concepts and findings.

Simpson ER. Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia

Fertil Steril 2002 Apr;77 Suppl 4:6-10

OBJECTIVE: To review the role of circulating C(19) steroids as precursors of estrogens in postmenopausal women.DESIGN: Review of current published literature.RESULT(S): In postmenopausal women as in men, estradiol no longer functions as a circulating hormone, because it ceases to be formed by the ovaries at the time of menopause. Estradiol continues to be formed in a number of extragonadal sites, however, including breast, bone, vascular smooth muscle, and various sites in the brain. At these sites of formation, local estradiol levels can be quite high, but the production rate is insufficient to affect the body in a global fashion; thus, estrogen action at these extragonadal sites of synthesis is primarily at a local level and serves a paracrine or even intracrine role.Because of this, in postmenopausal women as in men, circulating estrogen levels do not drive growth and development of target tissues. Instead, they reflect the metabolism of estradiol at these extragonadal sites. Estrogen that is not metabolized at these sites reenters the circulation, and, consequently, circulating levels of estradiol reflect its synthesis and action in extragonadal sites. Thus, they are reactive instead of proactive. An important difference between estrogen production at these extragonadal sites and estrogen that is synthesized in the ovary is that the former is absolutely dependent on a supply of circulating C(19) androgenic substrate.CONCLUSION(S): Circulating levels of testosterone begin to decline in the mid-reproductive years, and the levels of adrenal androgenic steroids, namely adrostenedione and DHEA, decrease throughout postmenopausal life. Therefore, the circulating levels of these adrogenic steroids may serve an important role in the maintenance of local estrogen synthesis, for example, in the bone and brain where estrogen has a profound influence on the maintenance of mineralization on the one hand, and possible cognitive function on the other.

Epidemiologic study of central obesity, insulin resistance and associated disturbances in the urban population of North India.

Singh RB, Niaz MA, Agarwal P, Beegum R, Rastogi SS, Singh NK. Heart Research Laboratory, Medical Hospital and Research Centre, Moradabad, India.

Acta Cardiol 1995;50(3):215-25

Central obesity in association with insulin resistance is a strong predictor of coronary artery disease (CAD) in South Asians; however the prevalence of central obesity and insulin resistance in Indians are unknown. Anthropometric measurements, dietary intakes, physical activity and prevalence of risk factors and CAD were obtained in 152 adults between 26-65 years of age (80 males, 72 females) selected by random sampling from urban population of Moradabad. The overall prevalence of central obesity was 539 per 1000 adults including 56.2% in males and 51.3% in females. The prevalence of glucose intolerance, diabetes mellitus, hypertension, hypertriglyceridemia and CAD were significantly higher in the higher quintiles of WHR above 0.88 compared to lower quintiles. Fasting and postprandial glucose, plasma insulin and triglycerides as well s total cholesterol and blood pressure were significantly higher in each of the upper quintile of WHR with increase in WHR compared to lowest quintile of WHR below 0.81. These findings indicate the existence of a modest degree of insulin resistance with a modest tendency to central obesity in the urban population of North India. The prevalence of CAD was significantly (p &lt; 0.01) higher among subjects with central obesity than in non-obese subjects (21.5 vs 3.2%). Underlying these findings, the prevalence of central obesity was significantly greater among sedentary and mild activity group compared to moderate and heavy activity group and per day energy expenditure during activity in the upper quintiles with WHR &gt; 0.88 was significantly less compared to energy expenditure in lower quintiles of WHR. Similarly dietary fat intake in the upper quintiles of WHR was also significantly higher than in the lower quintiles of WHR. These findings suggest that populations with higher prevalence of central obesity and CAD may be benefited with an aim to decrease central obesity.

Benign breast disease I: hormonal investigation.

Sitruk-Ware R, Sterkers N, Mauvais-Jarvis P.

Obstet Gynecol 1979 Apr;53(4):457-60

One hundred eighty-four patients with benign breast disease (BBD) were studied and compared with 50 normal women. All of the women had ovulatory cycles according to a biphasic basal body temperature and a plasma prolactin in the normal range. Their corpus luteum function was evaluated by way of plasma progesterone (P) and estradiol (E2) determinations at days 5, 7, and 9 of the hyperthermic phase. In the 184 patients, plasma P over plasma E2 ratio during the luteal phase was found significantly lower than in normal women. When the patients were grouped according to type of breast lesions, it appeared that plasma P was constantly lower in all groups than in the normal women, while plasma E2 was either normal or elevated in the groups of patients with adenosis tumors and increased nodularity of both breasts. From these results it may be postulated that an imbalance in the secretion of E2 and P by the corpus luteum is a constant finding in women with benign breast disease.

Dehydroepiandrosterone (DHEA) as a possible source for estrogen formation in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts.

Takayanagi R, Goto K, Suzuki S, Tanaka S, Shimoda S, Nawata H. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan

Mech Ageing Dev 2002 Apr;123(8):1107-14

A significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol. In subset analysis, strong positive correlation of serum DHEA-S and estrone with BMD was observed in postmenopausal women aged less than 69 years old. To study a possible role of DHEA-S in preventing osteoporosis, we characterized aromatase activity converting androgens to estrogens in human osteoblasts, because postmenopausal women maintain considerable levels of adrenal androgens. Glucocorticoids at 10(-9) to 10(-7) M induced transiently the expression of and the enzymatic activity of aromatase cytochrome P450 (P450AROM) in primary cultured osteoblasts. 1,25-Dihydroxyvitamin D3 (1,25-(OH)(2)D(3)) alone did not induce the aromatase activity, but enhanced and maintained the glucocorticoid-induced P450AROM gene expression. Analysis of the activity of P450AROM gene 1b (I.4) promoter, which is used dominantly in human osteoblasts, indicated that the region from -888 bp to -500 bp, which does not contain a typical vitamin D responsive element, is responsible for the enhancing effect of 1,25-(OH)(2)D(3). These results may suggest that adrenal androgen, DHEA, is converted to estrone in osteoblast by P450AROM, which is positively regulated by glucocorticoid and 1,25-(OH)(2)D(3), and is important in maintaining BMD in the sixth to the seventh decade, after menopause.

Brassica vegetables and breast cancer risk.

Terry, P., Wolk, A., Persson, I., Magnusson, C.

JAMA 2001 Jun 20; 285(23): 2975-7.

No abstract available.

Obesity type and clustering of insulin resistance-associated cardiovascular risk factors in middle-aged men and women.

Vanhala MJ, Pitkajarvi TK, Kumpusalo EA, Takala JK. Pieksamaki District Health Centre, Naarajarvi Health Station, Finland.

Int J Obes Relat Metab Disord 1998 Apr;22(4):369-74

OBJECTIVE: To examine different clusterings of the insulin resistance-associated cardiovascular risk factors with respect to different types of obesity. DESIGN: A screening programme for obesity (body mass index; BMI&gt; or =30 kg/m2) and abdominal adiposity (waist-to-hip ratio; WHR &gt; or = 1.00 in men and &gt; or = 0.88 in women).

SETTINGS: Pieksamaki District Health Centre and the Community Health Centre of the City of Tampere, Finland.

SUBJECTS: All volunteers were either aged 36, 41, 46 or 51 y (n=1148) and living in the town of Pieksamaki, with a control population of 162 subjects in the City of Tampere.

MAIN OUTCOME MEASURES: Different clusterings of: 1) hypertension (a systolic blood pressure &gt; or = 160 mmHg and/or a diastolic blood pressure &gt; or = 95 mmHg or concurrent drug treatment for hypertension); 2) hypertriglyceridaemia &gt; or = 1.70 mmol/l; 3) a low level of high-density-lipoprotein (HDL) cholesterol; &lt; 1.00 mmol/l in men, &lt; 1.20 mmol/l in women; 4) abnormal glucose metabolism (impaired glucose tolerance or non-insulin-dependent diabetes) and 5) hyperinsulinaemia with a fasting plasma insulin &gt; or = 13.0 mU/l.

RESULTS: The prevalence of a cluster consisting of dyslipidaemia (hypertriglyceridaemia and/or low HDL-cholesterol) and insulin resistance (abnormal glucose metabolism and/or hyperinsulinaemia) was found to be 4% in the control subjects, 18% in the abdominal adipose subjects (WHR &gt; or = 1.00 in men and &gt; or = 0.88 in women with a BMI &lt; 30 kg/m2), 28% in the 'pure' obese subjects (BMI&gt; or = 30 kg/m2 with WHR &lt; 1.00 in men and &lt; 0.88 in women), and 46% in the central obese subjects (subjects showing both 'pure' obesity and abdominal adiposity). The prevalence rates of the other clusterings of abnormalities varied similarly according to the type of obesity.

CONCLUSION: Clusterings of insulin resistance-associated abnormalities were related to the type of obesity in both middle-aged men and middle-aged women.

Fiber, lipids, and coronary heart disease. A statement for healthcare professionals from the Nutrition Committee, American Heart Association.

Van Horn, L.

Circulation 1997 Jun 17; 95(12): 2701-4.

No abstract available.

Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer.

Widschwendter M, Berger J, Muller HM, Zeimet AG, Marth C. Department of Obstetrics and Gynecology, University of Innsbruck, Austria. martin.widschwendter@uklibk.ac.at

J Mammary Gland Biol Neoplasia 2001 Apr;6(2):193-201

A growing body of evidence supports the hypothesis that the retinoic acid receptor beta2 (RAR-beta2) gene is a tumor suppressor gene which induces apoptosis and that the chemopreventive and therapeutic effects of retinoids are due to induction of RAR-beta2. During breast cancer progression, RAR-beta2 is reduced or even lost. It is known from studies of other tumor-suppressor genes that methylation of the 5'-region is the cause of loss of expression. Several groups demonstrated that this is also true for the RAR-beta2 in breast cancer by treating breast cancer cell lines with a demethylating agent and examining expression of the RAR-beta2 gene in response to a challenge with retinoic acid. Studies using sodium bisulfite genomic sequencing as well as methylation specific PCR showed that a number of breast cancer cell lines as well as breast cancer tissue showed signs of methylation. The RAR-beta2 gene was unmethylated in non-neoplastic breast tissue as well as in other normal tissues. A combination of retinoic acid with demethylating agents as well as with histone deacetylase inhibitors acts synergistically to inhibit growth. This review presents data that suggest that treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality. Both the time of commencement of chemoprevention and the choice of substances that are able either to prevent de novo methylation or to reverse methylation-caused gene silencing may be important considerations.

Dose-ranging study of indole-3-carbinol for breast cancer prevention.

Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP. Strang Cancer Prevention Center, New York, New York 10021, USA.

J Cell Biochem Suppl 1997;28-29:111-6

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.

Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids.

Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L, Li Y, Liu R, Lin B, Zhang XK. The Burnham Institute, La Jolla Cancer Research Center, California 92037, USA.

Mol Cell Biol 1997 Nov;17(11):6598-608

All-trans-retinoic acid (trans-RA) and other retinoids exert anticancer effects through two types of retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs). Previous studies demonstrated that the growth-inhibitory effects of trans-RA and related retinoids are impaired in certain estrogen-independent breast cancer cell lines due to their lower levels of RAR alpha and RARbeta. In this study, we evaluated several synthetic retinoids for their ability to induce growth inhibition and apoptosis in both trans-RA-sensitive and trans-RA-resistant breast cancer cell lines. Our results demonstrate that RXR-selective retinoids, particularly in combination with RAR-selective retinoids, could significantly induce RARbeta and inhibit the growth and induce the apoptosis of trans-RA-resistant, RAR alpha-deficient MDA-MB-231 cells but had low activity against trans-RA-sensitive ZR-75-1 cells that express high levels of RAR alpha. Using gel retardation and transient transfection assays, we found that the effects of RXR-selective retinoids on MDA-MB-231 cells were most likely mediated by RXR-nur77 heterodimers that bound to the RA response element in the RARbeta promoter and activated the RARbeta promoter in response to RXR-selective retinoids. In contrast, growth inhibition by RAR-selective retinoids in trans-RA-sensitive, RAR alpha-expressing cells most probably occurred through RXR-RAR alpha heterodimers that also bound to and activated the RARbeta promoter. In MDA-MB-231 clones stably expressing RAR alpha, both RARbeta induction and growth inhibition by RXR-selective retinoids were suppressed, while the effects of RAR-selective retinoids were enhanced. Together, our results demonstrate that activation of RXR can inhibit the growth of trans-RA-resistant MDA-MB-231 breast cancer cells and suggest that low cellular RAR alpha may regulate the signaling switch from RAR-mediated to RXR-mediated growth inhibition in breast cancer cells.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.

Writing Group for the Women's Health Initiative Investigators Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators. Division of Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817, USA.rossouw@nih.gov

JAMA. 2002 Jul 17;288(3):321-33.

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

Role of retinoid receptors in the prevention and treatment of breast cancer.

Yang LM, Tin-U C, Wu K, Brown P. Department of Medicine, The University of Texas Health Science Center at San Antonio, 78284, USA.

J Mammary Gland Biol Neoplasia 1999 Oct;4(4):377-88

Retinoids are vitamin A-related compounds that have been found to prevent cancer in animals and humans. In this review, we discuss the role of retinoids and their receptors in the treatment and prevention of breast cancer. The retinoid receptors are expressed in normal and malignant breast cells, and are critical for normal development. In breast cells, when bound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation. The mechanism by which retinoids inhibit breast cell growth has not been completely elucidated, however, retinoids have been shown to affect multiple signal transduction pathways, including IGF-, TGFbeta-, and AP-1-dependent pathways. Retinoids have also been shown to suppress the growth and prevent the development of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treated rats and in transgenic mice, and inhibit the growth of transplanted breast tumors. These promising preclinical results have provided the rationale to test retinoids in clinical trials for the treatment and prevention of breast cancer. Several retinoids, including all trans retinoic acid and 9-cis retinoic acid, have been shown to have modest activity in the treatment of breast cancer, and these agents are now in clinical trials in combination with cytotoxic agents and anti-estrogens. Another retinoid, 4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggest that 4-HPR may suppress breast cancer development in premenopausal women. Future clinical trials will focus on testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic and preventive efficacy.

[Anti-mutagenicity activity of dehydroepiandrosterone] [Article in Chinese]

Yang S, Fu Z, Wang F, Cao Y, Han R. Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.

Zhonghua Zhong Liu Za Zhi 2002 Mar;24(2):137-140

OBJECTIVE: The chemopreventive activity and mechanism of dehydroepiandrosterone (DHEA) were studied. METHODS: Model of 7, 12-dimethylbenz (alpha) anthracene (DMBA) induced breast carcinoma in Sprague-Dawley rats, uitra-violet (UV)-induced DNA damage and Salmonella mutation assay were used. RESULTS: In DMBA-induced rat mammary tumor model, the rats were orally given daily DHEA for 2 weeks before DMBA and continued for 10 weeks after DMBA administration. The results showed significant inhibition of tumor development by DHEA. The incidence of mammary carcinoma also decreased significantly on daily dose of oral 25 mg/kg DHEA with the mean tumor volume per rat also remarkably reduced by 92%. Moreover, 25 mg/kg DHEA treatment could significantly increase the carcinoma latency for about 3.5 weeks as compared with the control. Using polymerase chain reaction (PCR) assay, in vitro 10(-9) mol/L DHEA showed significant inhibitory effect on UV-induced DNA damage by 90%. In Ames test, DHEA was found to decrease DMBA and benzo (alpha) pyrene-induced TA98 and TA100 His(+) revertants markedly and the number of Salmonella clones were significantly reduced by 53.2% and 73.0% on dose of 5 &amp;mgr;g DHEA/plate. It was also shown that in vitro 10(-7) mol/L DHEA could also effectively inhibit the G-6-PDH activity, which might play an important role in its chemoprophylaxis activities. CONCLUSION: The results strongly prove that DHEA is a potent cancer chemoprophylaxis agent, which exhibits inhibitory potential on mutation and chemical carcinogen in vivo and in vitro.

Replacement of DHEA in aging men and women. Potential remedial effects.

Yen SS, Morales AJ, Khorram O. Department of Reproductive Medicine, University of California, San Diego, La Jolla 92093, USA.

Ann N Y Acad Sci 1995 Dec 29;774:128-42

DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant adverse effects. Further studies are needed to confirm and extend our current results, particularly the gender differences.

Hormonal abnormalities in obesity.

Zumoff B. Department of Medicine, Beth Israel Medical Center, New York, NY.

Acta Med Scand Suppl 1988;723:153-60

We have found a number of interesting hormonal abnormalities in obese men and women: 1) Obese women have normal levels of estrone, total estradiol, and total testosterone, but as a consequence of their subnormal levels of SHBG, their levels of free estradiol and free testosterone are significantly elevated. 2) Massive weight loss in obese women (to still elevated weight) results in normalization of the previously elevated free estradiol and free testosterone. 3) Obese women have normal plasma DHEA levels, but a significant, age-invariant decrease of the plasma DHEA/T ratio, which could be due to increased tissue activity of 3 beta-hydroxysteroid dehydrogenase. 4) Massive weight loss produces an age-dependent effect on DHEA levels in obese women: the levels increase to supranormal values in women around age 20, with diminishing increases at higher premenopausal ages and no increase at all at perimenopausal age. 5) Obese men have elevated levels of estrone and both free and total estradiol, and subnormal levels of free and total testosterone and of FSH; all these abnormalities are proportional to the degree of obesity. They also have relatively subnormal LH levels, i.e. normal in the face of hypotestosteronemia. The combination of these findings represents a state of mild hypogonadotropic hypogonadism (HHG), which we believe to be induced by the hyperestrogenemia. 6) Normalization of the estrogen levels of obese men, by suppression of adrenocortical secretion of aromatase substrates or by inhibition of aromatase, tends to normalize the HHG. 7) Massive weight loss in obese men normalizes their HHG without any decrease in plasma estrogen levels.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fibrocystic disease of breast and pituitary-thyroid axis function] [Article in Polish]

Zych F, Mizia-Stec K, Mucha Z, Zych-Twardowska E. II Katedry i Zakladu Patofizjologii Slaskiej Akademii Medycznej w Katowicach.

Pol Merkuriusz Lek 1996 Oct;1(4):227-8

The aim this study was to report findings on the concentrations of mean triiodothyroxine (T3), thyroxin (T4), thyroid stimulating hormone (TSH) and prolactin (Prl) in patients with benign mastopathy and in control group. All of the examined subjects were clinically euthyroid. The mean T4 concentrations in women with mastopathy (78.25 15.27 ng/ml) were significantly lower than in control group 88.73 15.27). The mean TSH and PRL concentration in women with mastopathy were higher, but not significantly, than in control women. This results indicate, that benign mastopathy seems to be connected with thyroid functions.