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Fibrocystic Breast Disease



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 < 0.001), whereas T4, free T4 and TSH concentrations were lower in BCF as compared to serum (p < 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 < 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


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


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


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 < 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 > 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 & 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 < 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 < 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 < 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 < 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 > 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> or =30 kg/m2) and abdominal adiposity (waist-to-hip ratio; WHR > or = 1.00 in men and > 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 > or = 160 mmHg and/or a diastolic blood pressure > or = 95 mmHg or concurrent drug treatment for hypertension); 2) hypertriglyceridaemia > or = 1.70 mmol/l; 3) a low level of high-density-lipoprotein (HDL) cholesterol; < 1.00 mmol/l in men, < 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 > 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 > or = 1.00 in men and > or = 0.88 in women with a BMI < 30 kg/m2), 28% in the 'pure' obese subjects (BMI> or = 30 kg/m2 with WHR < 1.00 in men and < 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 &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.

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