Hormonal therapy and genital tract cancer.

Wren B
Centre for the Management of the Menopause, Royal Hospital for Women, Paddington, Sydney, NSW, Australia.
Curr Opin Obstet Gynecol (United States) Feb 1996, 8 (1) p38-41

The use of hormonal replacement therapy following genital tract cancer is often denied to women because of the fear of increasing the risk of recurrence or new growth. The paucity of articles written on this subject during the past decade is an indication of the attitude of the medical profession to the needs of women suffering from symptoms of sex hormone deficiency. During 1994-1995 there were few articles published on the use of hormonal therapy to treat menopausal symptoms following genital tract cancer. Several articles, however, reviewed the relationship between hormones and genital tract cancer, some explored the value of antioestrogens in controlling recurrent or secondary disease, and a few others discussed the risk of developing uterine cancer when tamoxifen was used to manage postmenopausal breast cancer. Some suggestions are made that will allow women suffering from symptoms of hormone deficiency to receive alternative regimens of hormonal therapy. Maintaining quality of life without reducing the potential length of life is paramount in reaching a decision on the use of hormonal therapy following genital tract cancer.

Health consequences of short- and long-term postmenopausal hormone therapy.

Weiss NS
University of Washington, Seattle 98195, USA
nweiss@u.washington.edu
Clin Chem (United States) Aug 1996, 42 (8 Pt 2) p1342-4

Some women take an estrogen preparation for as long as several years to ease symptoms of the menopause. Such women appear to have little or no alteration in their risk of endometrial cancer, especially if they are also taking a progestogen, and no alteration in their risk of breast cancer. Similarly, the incidenc of fractures is unaffected by relatively short-term hormone use. The risk of ischemic heart disease also is reduced among women who currently take estrogens (with or without a progestogen), but the influence of duration of use on this association is uncertain. Postmenopausal women who take estrogens for an extended period of time (e.g., a decade or more) incur a sharply increased risk of cancer of the endometrium. This is largely abated by use of a progestogen for at least 10 days per month. Such long-term estrogen use, whether accompanied by a progestogen or not, may increase the risk of breast cancer slightly, but this is an area of great controversy, at present unresolved. The incidence of both myocardial infarction and fracture is substantially reduced in long-term users of menopausal hormones.

Current concepts in postmenopausal hormone replacement therapy.

Mayeaux EJ Jr; Johnson C
Department of Family Medicine, Lousiana State University Medical Center, Shreveport, USA.
J Fam Pract (United States) Jul 1996, 43 (1) p69-75

As more women are living longer, there is an increasing need for women to discuss hormone replacement therapy (HRT) with their physicians. This task is complicated by areas of scientific uncertainty and evolving data concerning the risks and benefits of HRT. Benefits of HRT that are supported by strong scientific evidence include relief from menopausal symptoms such as hot flashes, prevention of osteoporosis, cardioprotective effects, relief of urogenital atrophy, and decreased urinary incontinence. Benefits supported by observational evidence include improvement of emotional lability and depression, improved sense of well-being in patients with rheumatoid arthritis, increased dermal and total skin thickness, improved verbal memory skills, and decreased risk of colon cancer. Risks to consider include a possible increase in the incidence of breast cancer and an increase in endometrial cancer in women who have an intact uterus and do not receive a progestin. Women in various risk groups, such as those at risk for coronary artery disease, osteoporosis, or breast cancer, must consider the risk-to-benefit ratio for their own individual circumstances.

Regulation of estrogen/progestogen receptors in the endometrium.

Casper RF
Department of Obstetrics and Gynecology University of Toronto, Ontario, Canada.
Int J Fertil Menopausal Stud (United States) Jan-Feb 1996, 41 (1)p16-21

Patient acceptance of standard cyclic hormonal replacement therapy (HRT) has been poor. One major cause of non-acceptance is thought to be the resumption of menses as a result of induced withdrawal bleeding. In order to prevent bleeding, continuous combined estrogen and progestin HRT has been utilized. However, most publications report irregular breakthrough bleeding in a majority of patients receiving the continuous HRT regimen. The cause of the irregular bleeding remains unclear at present. It is known that the continuous presence of progestin causes down-regulation of estrogen and progestin receptors and endometrial atrophy. Endometrial atrophy may result in withdrawal of stromal support for blood vessels leading to dilatation and extravasation of blood. In addition, progestin has been implicated in neovascularization, possibly by stimulation of vascular endothelial growth factor (VEGF). Finally, programmed cell death and apoptosis appear to occur in endometrial stroma after prolonged exposure to progesterone and may contribute to breakthrough bleeding. We have developed a novel interrupted progestin HRT regimen in which estrogen is given continuously, but with progestin administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent total receptor down-regulation by allowing estrogen to up-regulate estrogen and progestin receptors during the progestin-free periods. Interrupting the progestin may also prove to be favorable in reducing neo-angiogenesis. Clinically, we have demonstrated low bleeding rates in menopausal women, and in premenopausal women on long-term GnRH-agonist treatment for endometriosis or severe PMS, in whom the interrupted regimen has been used for addback HRT. Further basic and clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance compared to continuous combined HRT.

Hormone replacement therapy and breast cancer risk.

Gambrell RD Jr br> Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, USA.
Arch Fam Med (United States) Jun 1996, 5 (6) p341-8

The role of estrogen therapy in the risk of breast cancer has been a concern for both physicians and patients. There is some evidence that women taking estrogen who develop breast cancer have a better prognosis. During 8 to 18 years of follow-up of 256 postmenopausal women with breast cancer from our hospital, median survival time was 84 months for those who never used estrogen, 80 months for past users, and 143 months for current users. More than 50 studies have shown that there is no increased risk of breast cancer even with long-term estrogen use, while some studies suggest an increased risk. Several studies indicate that when progestogens are added to estrogen therapy, there is a significant reduction in the risk of breast carcinoma. Indirect evidence is accumulating to show why added progestogen should decrease the risk of breast cancer. Preliminary studies further indicate that estrogen therapy, which has been contraindicated in breast cancer survivors in the past, may be safe, and added progestogens may decrease recurrences and deaths. Some medical oncologists and surgeons now advocate estrogen use in women with previous carcinoma of the breast.

Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women.

Paganini-Hill A; Dworsky R; Krauss RM
Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90031, USA.
Am J Obstet Gynecol (United States) Mar 1996, 174 (3) p897-902

OBJECTIVE: Our purpose was to assess the relationships of lipid and lipoprotein cholesterol levels to hormone replacement therapy and hormone levels in elderly women.

STUDY DESIGN: A sample of 292 postmenopausal women 55 to 99 years old (mean 76 years) was drawn from Leisure World Laguna Hills, California, an upper-middle-class, white independent-living population. We compared 84 women receiving unopposed estrogen replacement therapy and 38 women taking combination hormone replacement therapy with 170 women who had never used hormone replacement therapy. Nonparametric tests for differences in lipid and lipoprotein cholesterol levels among groups and multiple stepwise regression models were used.

RESULTS: Estrogen users (with and without progestin) had lower total and low-density lipoprotein cholesterol and higher high-density lipoprotein and high-density lipoprotein subfraction types 2, 2a, and 2b cholesterol levels. High density lipoprotein type 3 subfractions were lower in combination hormone replacement therapy users but higher in unopposed estrogen users relative to nonusers. The conjugated equine estrogen dose was negatively correlated with total (p = 0.0009) and low-density lipoprotein cholesterol (p <0.0001) levels and positively correlated to high-density lipoprotein cholesterol (p = 0.002) and its subfractions. The medroxyprogesterone acetate dose showed no consistent effect on cholesterol levels.

CONCLUSION: The associations found here reaffirm the significant role of estrogen replacement therapy on lipid and lipoprotein cholesterol levels and provide no evidence of a reduction in the beneficial effect of estrogen with the addition of a progestational agent to the replacement regimen.

Hormone replacement therapy as treatment of breast cancer--a phase II study of Org OD 14 (tibilone).

O'Brien M; Montes A; Powles TJ
Breast Unit, Royal Marsden Hospital, Sutton, Surrey, UK.
Br J Cancer (England) May 1996, 73 (9) p1086-8

Org OD 14 (tibilone) is a synthetic steroid, designed to combine the favourable effects of oestrogens, progestagens and androgens into a single substance for use as hormone replacement therapy (HRT). Given its antiovulatory properties, the ability to control menopausal symptoms and blocking action on progesterone receptors, Org OD 14 was considered as an agent with potential anti-cancer activity while at the same time helping existing menopausal symptoms. In this phase II study, 14 post-menopausal women with advanced or metastatic breast cancer, who had failed on tamoxifen, were treated with Org OD 14. The median duration of treatment was 12 weeks and all patients stopped because of progressive disease with or without toxicity. Vaginal bleeding occurred in four patients, three of whom had recently stopped tamoxifen. One response was seen: an 82-year-old patient had a partial response in an axillary soft tissue mass, improvement in liver function tests and an improvement in her performance status that lasted over 6 months. One patient with progressive disease on Org OD 14 improved on stopping the drug. In view of the vaginal bleeding, Org OD 14 should not be given to patients who have recently stopped tamoxifen.

Postmenopausal hormone therapy and breast cancer.

Speroff L
Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, USA.
Obstet Gynecol 1996 Feb;87(2 Suppl):44S-54S

Given the magnitude of the older female population, the possibility that postmenopausal hormone therapy is associated with an increased risk of breast cancer is an issue of great public and individual importance. Epidemiologic evidence indicates the possibility of a slightly increased risk of breast cancer associated with long durations of postmenopausal estrogen use. However, in a review of the literature, it is apparent that the epidemiologic data are contradictory and do not yield uniform and consistent results. It is further apparent that adding a progestin to a postmenopausal hormone program does not alter the findings compared with the use of estrogen alone. Reasons for this disagreement and lack of definitive evidence are detailed, and it is suggested that any impact of postmenopausal hormone therapy on the risk of breast cancer is unlikely to be great. Finally, the question of whether a woman who has had breast cancer should use postmenopausal hormones is addressed.

Future aspects of hormone-replacement therapy

Huber J.C.
Abt Gynakologische Endokrinologie, Sterilitatsbehandlung, Universitatskli nik Frauenheilkunde, Wahringer Gurtel 18-20, A-1090 Wien Austria
Acta Chirurgica Austriaca (Austria), 1996, 28/5 (282-284)

Background: The last 30 years' hormon-replacement therapy has mostly been directed towards substituting estrogen and progestogen.

Methods: A survey trying to demonstrate the therapeutic significance of replacing other hormones is given.

Results: The third sexual hormone, testosterone, was largely disregarded. As this steroid has a number of physiologic functions to fulfill it should be made use of in future replacement therapies. Another future aspect is to substitute not only sexual hormones but other hormones, which diminish with increasing age, as well. Among them are the growth hormone, dehydroepiandrosterone, and melatonin.

Conclusions: Sexual steroids are involved in many biologic compartments. Intensified, future, interdisciplinary cooperation with other fields could create therapeutic possibilities for a causative treatment of immunologic, dermatologic and ophthalmologic diseases that have so far not been linked with sexual steroids.

Neuroendocrine aspects of the menopause and hormone replacement therapy

Genazzani A.R.; Stomati M.; Spinetti A.; Bertolini S.; Nappi L.; Taponeco F.; Cela V.; D'Ambrogio G.; Hesch
Dept. of Obstetrics and Gynaecology, University of Pisa, Pisa Italy
Journal of Cardiovascular Pharmacology (USA), 1996, 28/Suppl. 5 (S58-S60)

Hypergonadotrophic hypogonadism in postmenopausal women induces neuroendocrine changes involving hypothalamic functions and secretion of pituitary hormones. Specific receptors for oestrogen, progestogen, and androgen are localized in the central nervous system, and sex steroid hormones exert a modulatory effect on the synthesis, release, and metabolism of neuroactive transmitters and their receptors. In particular, noradrenaline, dopamine, serotonin, acetylcholine, GABA, opioid peptides, neuropeptide Y, galanin, melatonin, and corticotrophin-releasing factor are influenced by sex steroids. Several disturbances originate from the withdrawal of sex steroids which, in the menopause, is associated with vasomotor instability, anxiety, insomnia, mood changes, migraine/headache, depression, loss of libido, reduced motor activity, loss of memory, and Alzheimer's disease. These represent possible clinical expressions of neuroendocrine modifications. There is particular interest in the higher prevalence of Alzheimer's dementia in postmenopausal women than in men. Hormone replacement therapy improves the cognitive performance and short- term memory of women with Alzheimer's type dementia. In fact, oestrogens increase the activity of acetylcholine transferase, which is the most important enzyme in the synthesis of acetylcholine. Therefore, the levels of acetylcholine are reduced, which is an important sign of Alzheimer's disease. Moreover, oestrogens improve dopaminergic tone, playing a protective role against Parkinson's disease in postmenopausal women.

Hormone therapy and phytoestrogens

Lien L.L.; Lien E.J.
Dept. of Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, CA 90033 USA
Journal of Clinical Pharmacy and Therapeutics (United Kingdom), 1996, 21/2 (101-111)

As ageing progresses the levels of sex hormones decrease in the human body. In the male population, the decrease or absence of testosterone leads to decreased strength and stamina, thin bones and a low sex drive

(1). In the female population, the immediate symptoms of menopause include irregular periods, painful sexual intercourse due to vaginal dryness, hot flushes and night sweats

(2). Lack of oestrogen also leads to the risk of developing osteoporosis and cardiovascular diseases. In this report, the authors will mainly discuss the effects of hormone therapy (HT) in menopausal women. Available current clinical data on the effects of calcium supplementation with and without HT, exercise, exercise plus calcium and exercise with HT on bone loss are presented. The effects of transdermal and oral oestrogen therapy (OT) on serum lipids are discussed. Commercially-available HT products, their indications, dosages, contra-indications, side-effects and drug interactions are compared. Alternative therapies for menopausal symptoms with Chinese traditional herbs, and a comparison of the molecular structures of phytoestrogens with estradiol and diethylstilbestrol are examined

(3, 4). A list of medicinal herbs and foods reported toelicit an oestrogenic response in animals is compiled.

The effects of hormone replacement therapy on plasma vitamin E levels in post-menopausal women

Wu J.; Norris L.A.; Wen Y.C.; Sheppard B.L.; Feely J.; Bonnar J.
Department of Obstetrics/Gynaecology, Trinity College Centre, St. James's Hospital, Dublin 8 Ireland
European Journal of Obstetrics Gynecology and Reproductive Biology (Ireland), 1996, 66/2 (151-154)

Objective: To measure vitamin E levels in post-menopausal women before and after HRT, compared with levels in pre-menopausal women.

Design: Post-menopausal women (n = 21) had plasma vitamin E levels measured before treatment and after 6 and 12 months treatment with HRT (2 mg 17-beta-oestradiol and 1 mg norethisterone acetate). The pre-menopausal group (n = 20) had plasma vitamin E levels measured at day 15-18 of the menstrual cycle.

Results: There was no significant difference in vitamin E levels between the pre-menopausal group and the post-menopausal group. Plasma vitamin E levels were not significantly altered by 12 months HRT, Conclusion: Post-menopausal women did not have altered levels of vitamin E compared with pre-menopausal women. Similarly HRT has no effect on plasma vitamin E levels. We conclude therefore that HRT does not reduce vitamin E levels in a similar manner to oral contraceptives and consequently post-menopausal women are unlikely to need a vitamin E supplement.

Effects of hormonal therapies and dietary soy phytoestrogens on vaginal cytology in surgically postmenopausal macaques

Cline J.M.; Paschold J.C.; Anthony M.S.; Obasanjo I.O.; Adams M.R.
Department of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040 USA
Fertility and Sterility (USA), 1996, 65/5 (1031-1035)

Objective: To evaluate the effects of conjugated equine estrogens, medroxyprogesterone acetate (MPA), conjugated equine estrogens combined with MPA, tamoxifen, and soybean estrogens on vaginal cytology in surgically postmenopausal cynomolgus macaques (Macaca fascicularis).

Design: Randomized long-term experimental trial.

Setting: Cytologic samples were taken from animals in two long-term randomized studies of the effects of hormonal and dietary effects on atherosclerosis.

Patients: Surgically postmenopausal cynomolgus macaques. Interventions: Conjugated equine estrogens, MPA, conjugated equine estrogens combined with MPA, tamoxifen, and soybean estrogens were given via the diet, at doses scaled from those given to women.

Main Outcome Measure: Vaginal cytologic maturation index.

Results: Conjugated equine estrogens elicited a marked maturation effect, which was antagonized partially by the addition of MPA. Tamoxifen produced a lesser estrogenic response. The cytologic pattern in animals given soybean estrogens or MPA alone did not differ from that of controls.

Conclusion: Soybean estrogens at the doses given do not exert an estrogenic effect on the vagina of macaques. Conjugated equine estrogens are potent inducers of vaginal keratinization in this model; tamoxifen has a lesser effect. Medroxyprogesterone acetate partially antagonizes the effects of conjugated equine estrogens, and has no effect when given alone. The results support the possibility that soybean estrogens may be a 'tissue-selective' estrogen with minimal effects on the reproductive tract.

Dietary and behavioral determinants of menopause

Gold E.B.
Community/International Health Dept., School of Medicine, University of California, Davis, CA 95616 USA
Clinical Consultations in Obstetrics and Gynecology (USA), 1996, 8/1 (21-26)

1. Black and Hispanic women have been observed to experience natural menopause at an earlier age than white women, despite increased body mass, whereas Asian women have been observed to have a lower frequency of hot flushes than white women, despite lower serum estradiol levels.

2. Women who smoke have consistently been shown to experience menopause earlier than nonsmokers and to have a shorter perimenopause, and a dose-response relationship in this association has been shown. Little is known about the relationship of passive smoke exposure to age at menopause or whether smoking increases the frequency or severity of menopausal symptoms.

3. Although some studies show that increased body mass and upper body fat are associated with later age at menopause, some studies do not confirm this. Further research is needed on the independent effects of body mass and composition on frequency and severity of menopausal symptoms.

4. Shorter and more variable menstrual cycles in early adulthood and increased parity and oral contraceptive use have all been associated with later age at menopause.

5. Age at menarche, previous spontaneous abortions, age at first birth, and history of breast- feeding have all been shown not to be associated with age at menopause.

6. The effect of physical activity on age at menopause is unknown, but participation in an exercise program reduced the vasomotor symptoms associated with menopause.

7. Lower social class has been associated with earlier menopause, but nothing is known about the relationship of occupational exposures to age at menopause or frequency or severity of menopausal symptoms.

8. Dietary phytoestrogens have estrogenic activity and may compete with estradiol for binding to estrogen receptors and affect plasma estradiol, FSH and LH levels in premenopausal women and have been shown to reduce hot flashes in one small study of postmenopausal women.

A review of the clinical effects of phytoestrogens

Knight D.C.; Eden J.A.
Frank Rundle House, Royal Hospital for Women, 188 Oxford Street, Paddington, NSW 2021 Australia
Obstetrics and Gynecology (USA), 1996, 87/5 II Suppl. (897-904)

Objective: To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans.

Data Sources: The MEDLINE data base for the years 1980-1995 and reference lists of published articles were searched for relevant English-language articles concerning phytoestrogens, soy products, and diets with high-phytoestrogen content.

Methods of Study Selection: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case-control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area.

Tabulation, Integration, and Results: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis.

Conclusion: This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds.

Molecular effects of genistein on estrogen receptor mediated pathways

Wang T.T.Y.; Sathyamoorthy N.; Phang J.M.
Lab Nutritional Molecular Regulation, NCI-Frederick Cancer Res Dev Ctr, NIH, Frederick, MD 21702-1201 USA
Carcinogenesis (United Kingdom), 1996, 17/2 (271-275)

Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA expression at concentrations as low as 10-8 M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with (3H)estradiol binding to the estrogen receptor with 50% inhibition at 5 X 10-7 M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The effect of genistein on growth of MCF-7 cells was also examined. Genistein produced a concentration-dependent effect on the growth of MCF-7 cells. At lower concentrations (10-8-10-6 M) genistein stimulated growth, but at higher concentrations (>10-5 M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.

Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer

Barnes S.; Peterson T.G.; Coward L.
Department of Pharmacology, Birmingham Medical Center, University of Alabama, 1670 University Boulevard, Birmingham, AL 35294-0019 USA
J Cell Biochem Suppl 1995;22:181-7

Pharmacologists have realized that tyrosine kinase inhibitors (TKI) have potential as anti-cancer agents, both in prevention and therapy protocols. Nonetheless, concern about the risk of toxicity caused by synthetic TKIs restricted their development as chemoprevention agents. However, a naturally occurring TKI (the isoflavone genistein) in soy was discovered in 1987. The concentration of genistein in most soy food materials ranges from 1-2 mg/g. Oriental populations, who have low rates of breast and prostate cancer, consume 20-80 mg of genistein/day, almost entirely derived from soy, whereas the dietary intake of genistein in the US is only 1-3 mg/day. Chronic use of genistein as a chemopreventive agent has an advantage over synthetic TKIs because it is naturally found in soy foods. It could be delivered either in a purified state as a pill (to high-risk, motivated patient groups), or in the form of soy foods or soy-containing foods. Delivery of genistein in soy foods is more economically viable ($1.50 for a daily dose of 50 mg) than purified material ($5/day) and would require no prior approval by the FDA. Accordingly, investigators at several different sites have begun or are planning chemoprevention trials using a soy beverage product based on SUPRO(TM), an isolated soy protein manufactured by Protein Technologies International of St. Louis, MO. These investigators are examining the effect of the soy beverage on surrogate intermediate endpoint biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining potential SIEBs in patients at risk for prostate cancer, and determining whether the soy beverage reduces the incidence of cancer recurrence. These studies will provide the basis for formal Phase I, Phase II and Phase III clinical trials of genistein and soy food products such as SUPRO(TM) for cancer chemoprevention.

Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat

Murkies A.L.; Lombard C.; Strauss B.J.G.; Wilcox G.; Burger H.G.; Morton M.S.
Brighton Medical Clinic, 26 Carpenter St., Brighton, Vic. 3186 Australia
Maturitas (Ireland), 1995, 21/3 (189-195)

Plants contain compounds with oestrogen-like action called phytoestrogens. Soy contains daidzin, a potent phytoestrogen, and wheat flour contains less potent enterolactones. We aimed to show in 58 postmenopausal women (age 54, range 30-70 years) with at least 14 hot flushes per week, that their daily diet supplemented with soy flour (n = 28) could reduce flushes compared with wheat flour (n = 30) over 12 weeks when randomised and double blind. Hot flushes significantly decreased in the soy and wheat flour groups (40% and 25% reduction, respectively <0.001 for both) with a significant rapid response in the soy flour group in 6 weeks (P < 0.001) that continued. Menopausal symptom score decreased significantly in both groups (P < 0.05). Urinary daidzein excretion confirmed compliance. Vaginal cell maturation, plasma lipids and urinary calcium remained unchanged. Serum FSH decreased and urinary hydroxyproline increased in the wheat flour group.

Soy and experimental cancer: Animal studies

Hawrylewicz E.J.; Zapata J.J.; Blair W.H.
Department of Research, Mercy Hospital/Medical Center, Chicago, IL 60616 USA
Journal of Nutrition (USA) , 1995, 125/3 SUPPL. (698S-708S)

Studies are reviewed that report consumption of soy protein diets inhibits the growth of various tumors in rats. The inhibitory effect has been attributed to the phytoestrogens (genistein and diadzein) or protein kinase inhibitor in soy protein products. Recent studies indicate that additional factors in soy protein products may also contribute to the inhibition of tumorigenesis, namely the deficiency of the essential amino acid methionine. Metastatic growth to the lungs of a primary rhabdomyosarcoma tumor was inhibited by feeding a soy protein diet. The effect was reversed by methionine fortification of the diet. Carcinogen-induced mammary tumor development was inhibited during the promotional phase in rats fed soy protein isolate diet and reversed with a methionine-supplemented diet. Additional studies demonstrated that after excision of the primary mammary tumor, growth of additional tumors was inhibited when the diet was changed from casein to soy protein isolate. Histopathologic evaluation of the mammary tumors revealed more benign fibroadenomas and lower-grade adenocarcinomas in the soy protein group. Before carcinogen administration (at 7 weeks of age), ornithine decarboxylase activity and polyamine concentrations in the rat mammary epithelium were significantly lower in the soy protein group. These data suggest an inhibitory effect on mammary epithelial growth in the soy-protein-fed group.

Aromatase in bone cell: Association with osteoporosis in postmenopausal women

Nawata H.; Tanaka S.; Tanaka S.; Takayanagi R.; Sakai Y.; Yanase T.; Ikuyama S.; Haji M.
Third Dept. of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Fukuoka 812 Japan
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 53/1-6 (165-174)

To clarify the possible action of adrenal androgen on bone cell, the existence, characteristics and regulation of aromatase in human osteoblast-like osteosarcoma cells (HOS) and primary cultured osteoblast-like cells from normal human bones (HO) were examined in this study. 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 (E2). In subset analysis, strongly positive correlation of serum DHEA-S and estrone (E1) with BMD was observed in postmenopausal women aged less than 69 years old. Administration of DHEA to ovariectomized rat significantly increased BMD and decreased relative osteoid volume in femur. These in vivo findings strongly suggested that serum adrenal androgen may be converted to estrogen in peripheral organ, especially, osteoblast and be important steroids to maintain BMD. (3H)DHEA was converted to (3H)androstenedione and (3H)androstenedione to (3H)estrone in primary cultured human osteoblast. Osteoblast-like cells showed aromatase activity, and an apparent K(m) and the V(max) were 4.74 plus or minus 0.78 nM (mean plus or minus SD, n = 3) and 0.83 plus or minus 0.79 fmol/mg protein/h for HOS, and 4.6 plus or minus 2.9 nM and 279 plus or minus 299 fmol/mg protein/h (mean plus or minus SD, n = 19) for HO, respectively. The aromatase activity was significantly increased by dexamethasone in a dose-dependent manner. Reverse transcription-polymerase chain reaction analysis revealed that dexamethasone increased the transcript of P450(AROM) gene. Osteoblast-specific promoters were also determined. Dexamethasone and 1alpha,25-dihydroxyvitamin D3 synergistically enhanced aromatase activity and P450(AROM) mRNA expression. These results demonstrate that adrenal androgen, DHEA, is converted to E1 in osteoblast by P450(AROM) which is positively regulated by glucocorticoid and 1alpha,25-dihydroxyvitamin D3 and important to maintain BMD in the 6 to 7th decade, after menopause.

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