Dietary Phytoestrogens Are Not Associated with Risk of Overall Breast Cancer But Diets Rich in Coumestrol Are Inversely Associated with Risk of Estrogen Receptor and Progesterone Receptor Negative Breast Tumors in Swedish Women1,2

Dietary Phytoestrogens Are Not Associated with Risk of Overall Breast Cancer But Diets Rich in Coumestrol Are Inversely Associated with Risk of Estrogen Receptor and Progesterone Receptor Negative Breast Tumors in Swedish Women1,2
Maria Hedelin3,4,*, Marie Löf3, Marita Olsson3, Herman Adlercreutz5, Sven Sandin3 and Elisabete Weiderpass3,4,6

3 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden; 4 Department of Genetic Epidemiology, Samfundet Folkhälsan, SE-00250 Helsinki, Finland; 5 Institute for Preventive Medicine, Nutrition and Cancer, Folkhälsan Research Center and Division of Clinical Chemistry, University of Helsinki, FIN-00014 Helsinki, Finland; and 6 Cancer Registry of Norway, NO-0310 Oslo, Norway

* To whom correspondence should be addressed. E-mail: maria.hedelin@ki.se.

Results from epidemiological and experimental studies indicate that phytoestrogens may protect against breast cancer. Because one of the biological effects of phytoestrogens is probably estrogenic, it's possible that the preventive effect on breast cancer differs by estrogen receptor (ER) or progesterone receptor (PR) status of the tumor. We evaluated the associations between dietary phytoestrogen (isoflavonoids, lignans, and coumestrol) intake and risk of breast cancer and whether the ER/PR statuses of the tumor influence this relationship. In 1991–2 a prospective population-based cohort study among Swedish pre- and postmenopausal women was performed, making questionnaire data available for 45,448 women. A total of 1014 invasive breast cancers were diagnosed until December 2004. Cox proportional hazards models were performed to estimate multivariate risk ratios, 95% CI for associations with risk of breast cancer. Intakes of lignan, isoflavonoid, or coumestrol were not associated with breast cancer risk overall or before or after 50 y of age. The effects of lignans or isoflavonoids were independent of receptor status. However, intake of coumestrol was associated with decreased risk of receptor negative tumors (ER–PR–) but not positive tumors. The risk of ER–PR– tumors was significantly lower (50%) in women with intermediate coumestrol intake compared with those who did not consume any. In conclusion, we found no association between intake of isoflavonoids or lignans and breast cancer risk. Our results of a decreased risk of ER–PR– tumors in women with intermediate intake of coumestrol could be due to chance because of the low intake. The results should be confirmed in other studies.

Because one of the well established consequences of calcium influx into cells is rapid release of the hormone prolactin, they then determined whether the xenoestrogens had the same effect on prolactin secretion, using a standard concentration for each compound of 10-8 molar. Some did--DES, bisphenol A, nonylphenol and coumestrol. However the organochlorine pesticides had either a delayed effect or, in the case of DDE, no effect on prolactin secretion at that concentration (although it did at others).

They then studied the dose-response characteristics for the prolactin secretion response. Their results for four of the xenoestrogens are shown in the graph below. Each graph displays the increase in prolactin secretion, as a percent of control, for the range of doses tested.






These graphs show the average response to exposure to a range of concentrations of 4 estrogenic compounds, expressed as a percent of the response of the control. Thus a value of 100 is equivalent to the control's response. Small vertical lines on the bars are standard errors.

Of all the compounds tested, including estradiol, bisphenol A had the largest impact at the lowest dose tested. Exposure to bisphenol A at 10-12 caused a doubling of the amount of prolactin secretion. The smallest effects were seen for exposure to the phytoestrogen coumestrol. The only concentration that differed significantly from the control as the highest,10-8, at which it doubled prolactin.

Their results raise many issues, nonetheless. In their experiments, For example, Wozniak et al. show that prolactin levels increase with xenoestrogen exposure. As they comment in their discussion, prolactin increases in people have been associated with delays in puberty, interference with ovulation, decreases in libido and fertility, and increases in cell proliferation. Prolactin is also an important signaling molecule for the immune system and the lining of the pregnant uterus.

http://www.ourstolenfuture.org/NEWSCIENCE/lowdose/2005/2005-0115wozniaketal.htm

Endocrine Toxicology. Evaluation of a Tier I Screening Battery for Detecting Endocrine-Active Compounds (EACs) Using the Positive Controls Testosterone, Coumestrol, Progesterone, and RU486

Authors: O'Connor, John C.1; Davis, Leonard G.1; Frame, Steven R.1

Source: Toxicological Sciences, Volume 54, Number 2, April 2000 , pp. 338-354(17)

Publisher: Oxford University Press

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Abstract:
After previously examining 12 compounds with known endocrine activities, we have now evaluated 4 additional compounds in a Tier I screening battery for detecting endocrine-active compounds (EACs): a weak estrogen receptor (ER) agonist (coumestrol; COUM), an androgen receptor (AR) agonist (testosterone; TEST), a progesterone receptor (PR) agonist (progesterone; PROG), and a PR antagonist (mifepristone; RU486). The Tier I battery incorporates 2 short-term in vivo tests (5-day ovariectomized female battery; 15-day intact male battery) and an in vitro yeast transactivation system (YTS). The Tier I battery is designed to identify compounds that have the potential to act as agonists or antagonists to the estrogen, androgen, progesterone, or dopamine receptors; steroid biosynthesis inhibitors (aromatase, 5agr-reductase, and testosterone biosynthesis); or compounds that alter thyroid function. In addition to the Tier I battery, a 15-day dietary restriction experiment was performed using male rats to assess confounding due to treatment-related decreases in body weight. In the Tier I female battery, TEST administration increased uterine weight, uterine stromal cell proliferation, and altered hormonal concentrations (increased serum testosterone [T] and prolactin [PRL]; and decreased serum FSH and LH). In the male battery, TEST increased accessory sex gland weights, altered hormonal concentrations (increased serum T, dihydrotestosterone [DHT], estradiol [E2], and PRL; decreased serum FSH and LH), and produced microscopic changes of the testis (Leydig cell atrophy and spermatid retention). In the YTS, TEST activated gene transcription in the yeast containing the AR or PR. In the female battery, COUM administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height, and increased serum PRL concentrations. In the male battery, COUM altered hormonal concentrations (decreased serum T, DHT, E2; increased serum PRL) and, in the YTS, COUM activated gene transcription in the yeast containing the ER. In the female battery, PROG administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height and altered hormonal concentrations (increased serum progesterone and decreased serum FSH and LH). In the male battery, PROG decreased epididymis and accessory sex gland weights, altered hormonal concentrations (decreased serum T, PRL, FSH, and LH; increased serum progesterone and E2), and produced microscopic changes of the testis (Leydig cell atrophy). In the YTS, PROG activated gene transcription in the yeast containing the AR or PR. In the female battery, RU486 administration increased uterine weight and decreased uterine stromal cell proliferation. In the male battery, RU486 decreased epididymis and accessory sex gland weights and increased serum FSH and LH concentrations. In the YTS, RU486 activated gene transcription in the yeast containing the ER, AR, or PR. Dietary restriction data demonstrate that confounding due to decrements in body weight are not observed when body weight decrements are 10% or less in the Tier I male battery. In addition, minimal confounding is observed at body decrements of 15% (relative liver weight, T3, and T4). Hence, compounds can be evaluated in this Tier I at levels that produce a 10% decrease in body weight without confounding of the selected endpoints. Using the responses obtained for all the endpoints in the Tier I battery, a distinct “fingerprint” was produced for each type of endocrine activity against which compounds with unknown activity can be compared. These data demonstrate that the described Tier I battery is useful for identifying EACs and they extend the compounds evaluated to 16.

http://www.ingentaconnect.com/content/oup/toxsci/2000/00000054/00000002/art00338

Some of these staged experiements using synthetic molecules in ordet to reduce variability, do not agree with what experience tells us from studies with real people and diets.