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The Million Women Study (MWS) and the Women's Health Initiative (WHI) Study reveal an increased breast cancer risk and a higher relative risk for cardiovascular diseases in women on hormone replacement therapy (HRT) in comparison with control groups. For this reason, the WHI study was terminated prematurely. From the point of view of the internist, it would appear that, on the basis of the results of these studies, prophylactic treatment with estrogens and progesterone is no longer indicated. It must, however, be noted that numerous aspects are still unclear. This therefore means that in patients with severe menopausal symptoms giving rise to a high level of distress, HRT continues to be justified over the short term after a current cardiovascular risk or relevant tumor disease has been excluded.
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PMID:[Hormone replacement therapy and the risk of developing breast cancer]. 1535 2

Patients seeking alternatives to hormone replacement are increasingly using non-prescription phytoestrogen supplements. The potential of these herbal remedies to prevent bone loss, heart disease, menopausal symptoms or breast cancer has been a focus of attention in scientific and lay literature. It is important to understand the effects of phytoestrogens, particularly whether excess exposure can promote hyperplasia or neoplasia of breast tissue. We report the case of a man diagnosed with breast cancer whose history was notable for extensive use of supplemental phytoestrogens and the absence of family history of breast cancer or BRCA1/BRCA2 mutation. In conclusion, breast tissue effects of phytoestrogens remain unclear. The increasing popularity and availability of phytoestrogen dietary supplements necessitates additional research in order to counsel patients regarding their safety and efficacy.
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PMID:Phytoestrogen supplementation: a case report of male breast cancer. 1554 40

Premenstrual syndrome (PMS) and the perimenopause are each difficult conditions to manage. When they co-exist the difficulty is more than doubled. Understanding and recognising the differences and the similarities between these conditions should enable clinicians to provide appropriate treatment and significantly improve women's quality of life. Distinction between the two can be difficult. Anecdotally women seem more prone to PMS symptoms during the perimenopause, or at least they tolerate the symptoms less well. Symptoms of the perimenopause arise from falling oestrogen levels with irregular ovulation, resulting in symptoms of oestrogen lack and heavy irregular periods. Symptoms of the perimenopause are thus relieved by the administration of oestrogen. Premenstrual syndrome frequently results when ovulation occurs. PMS appears to be due directly to the progesterone produced following ovulation in women who have enhanced sensitivity to this steroid. Treatment can thus be achieved by suppressing ovulation or reducing progesterone sensitivity; the latter seems achievable by the administration of selective serotonin re-uptake inhibitors. Ovulation can be suppressed by a variety of methods and oestrogen is an approach which is frequently employed. This will also effectively treat menopausal symptoms. The main problem with using oestrogen is that a progestogen must be administered to prevent endometrial neoplasia; this can result in a return of the PMS symptoms. This article reviews the difficulties encountered in women with both disorders and provides a suggested management strategy.
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PMID:PMS in the perimenopause. 1566 51

Novel estrogenic therapies are needed that ameliorate menopausal symptoms and have the bone-sparing effects of endogenous estrogens but do not promote breast or uterine cancer. Recent evidence suggests that selective activation of the estrogen receptor (ER)-beta subtype inhibits breast cancer cell proliferation. To establish whether ERbeta-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERbeta selective. MF101 promoted ERbeta, but not ERalpha, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERbeta. The ERbeta selectivity was not due to differential binding because MF101 binds equally to ERalpha and ERbeta. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ERalpha from ERbeta when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERbeta to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ERalpha-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model. Our results demonstrate that herbal ERbeta-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes.
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PMID:Selective activation of estrogen receptor-beta transcriptional pathways by an herbal extract. 1709 96

The last 7 years have seen over seven times as many publications indexed by Medline dealing with pomegranate and Punica granatum than in all the years preceding them. Because of this, and the virtual explosion of interest in pomegranate as a medicinal and nutritional product that has followed, this review is accordingly launched. The pomegranate tree, Punica granatum, especially its fruit, possesses a vast ethnomedical history and represents a phytochemical reservoir of heuristic medicinal value. The tree/fruit can be divided into several anatomical compartments: (1) seed, (2) juice, (3) peel, (4) leaf, (5) flower, (6) bark, and (7) roots, each of which has interesting pharmacologic activity. Juice and peels, for example, possess potent antioxidant properties, while juice, peel and oil are all weakly estrogenic and heuristically of interest for the treatment of menopausal symptoms and sequellae. The use of juice, peel and oil have also been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasion and angiogenesis. These may be associated with plant based anti-inflammatory effects, The phytochemistry and pharmacological actions of all Punica granatum components suggest a wide range of clinical applications for the treatment and prevention of cancer, as well as other diseases where chronic inflammation is believed to play an essential etiologic role.
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PMID:Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. 1715 65

Soy supplements are often consumed by women for alleviating menopausal symptoms or for the perceived protective effects against breast cancer. More concerning is the concurrent consumption of soy isoflavones with tamoxifen (TAM) for prevention or treatment of breast cancer. We previously described a T47D:A18/protein kinase C (PKC)alpha TAM-resistant tumor model that exhibits autonomous growth and estradiol-induced tumor regression. We compared the estrogenicity of the isoflavones genistein, daidzein, and the daidzein metabolite equol in the parental T47D:A18 and T47D:A18/PKC alpha cell lines in vitro and in vivo. Whereas equol exerts estrogenic effects on T47D:A18 cells in vitro, none of the isoflavones stimulated T47D:A18 tumor growth. T47D:A18/PKC alpha tumor growth was partially stimulated by genistein, yet partially inhibited by daidzein. Interestingly, coadministration of TAM with either daidzein or genistein produced tumors of greater size than with TAM alone. These findings suggest that simultaneous consumption of isoflavone supplements with TAM may not be safe.
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PMID:The effect of the phytoestrogens genistein, daidzein, and equol on the growth of tamoxifen-resistant T47D/PKC alpha. 1764 Jan 69

Estrogen is a potent stimulus for growth in its target organs: the uterus, vagina, and some estrogen receptor-positive breast cancers. However, estrogen is also able to control menopausal symptoms and maintain bone density in postmenopausal women. Until recently, there was also believed to be a link between estrogen and the prevention of cardiovascular disease. For these reasons, hormone replacement therapy (HRT) with an orally active estrogen and progesterone has been used routinely for more than 50 years to maintain physiologic homeostasis after menopause. Not surprisingly, HRT increases the risk of developing breast cancer. The link between estrogen and breast cancer growth served as the incentive to develop long-term tamoxifen therapy and, subsequently, the aromatase inhibitors (AIs) as successful "anti-estrogenic" treatments. Unfortunately, the consequence of exhaustive therapy is drug resistance. Laboratory studies have defined the evolution of tumor drug resistance to tamoxifen, raloxifene (used for breast and osteoporosis chemoprevention), and the AIs. Remarkably, the long-term exposure of breast cancers to antihormonal therapy also exposes a vulnerability that is being exploited in the clinic. Years of antihormonal therapy alters the cellular response mechanism to estrogen. Normally, estrogen is classified as a survival signal in breast cancer, but in sensitive antihormone-resistant cells, estrogen induces apoptosis. When resistant cells are killed, antihormonal therapy is once again effective. This new targeted approach to the treatment of metastatic breast cancer could open the door to novel approaches to treatment with drug combinations.
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PMID:Low-dose estrogen therapy to reverse acquired antihormonal resistance in the treatment of breast cancer. 1862 8

Systemic estrogen depletion is the mechanism of action of most endocrine treatment strategies, and a common side effect of most chemotherapy regimens that are currently used to treat invasive breast cancer. The ensuing immediate and profound decline in estrogen levels is, however, often associated with considerable climacteric complaints. While oral estrogen add-back therapy is effective in alleviating menopausal symptoms, it is feared that it might also promote tumor cell growth. This concern is largely based on circumstantial evidence from large trials in healthy women, in which hormone replacement therapy (HRT) resulted in a slight, albeit significant, increase in incident breast cancer. In breast cancer survivors, however, evidence from studies remains controversial. Despite these caveats, the severity of symptoms and the lack of effective alternatives still cause many women to opt for HRT. Nevertheless, HRT cannot generally be recommended as first-line therapy for climacteric complaints in women with a history of breast cancer. It may, however, be a valid option for selected women with climacteric symptoms refractory to previous non-hormonal treatments. In these cases, an individualized risk-benefit analysis is imperative before treatment initiation, and a treatment duration of less than 5 years with intermittent withdrawal attempts should be aimed for.
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PMID:Climacteric Complaints after Breast Cancer - Is HRT an Option? 2082 41

A high intake of fruits and vegetables is associated with a lower risk of cancer. In this context, considerable attention is paid to Asian populations who consume high amounts of soy and soy-derived isoflavones, and have a lower risk for several cancer types such as breast and prostate cancers than populations in Western countries. Hence, interest focuses on soyfoods, soy products, and soy ingredients such as isoflavones with regard to their possible beneficial effects that were observed in numerous experiments and studies. The outcomes of the studies are not always conclusive, are often contradictory depending on the experimental conditions, and are, therefore, difficult to interpret. Isoflavone research revealed not only beneficial but also adverse effects, for instance, on the reproductive system. This is also the case with tumor-promoting effects on, for example, breast tissue. Isoflavone extracts and supplements are often used for the treatment of menopausal symptoms and for the prevention of age-associated conditions such as cardiovascular diseases and osteoporosis in postmenopausal women. In relation to this, questions about the effectiveness and safety of isoflavones have to be clarified. Moreover, there are concerns about the maternal consumption of isoflavones due to the development of leukemia in infants. In contrast, men may benefit from the intake of isoflavones with regard to reducing the risk of prostate cancer. Therefore, this review examines the risks but also the benefits of isoflavones with regard to various kinds of cancer, which can be derived from animal and human studies as well as from in vitro experiments.
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PMID:Risks and benefits of dietary isoflavones for cancer. 2143 20

In breast cancer, the interaction between estrogen-producing breast adipose fibroblasts (BAFs) and estrogen-dependent epithelial tumor cells is pivotal. Local estrogen production is catalyzed by aromatase, which is differentially regulated in disease-free and tumorigenic breast tissue. The use of aromatase inhibitors to block local estrogen production has proven effective in treatment of estrogen-dependent breast cancer. However, a major problem during breast cancer treatment is the sudden onset of menopause and many women seek for alternative medicines, such as the soy isoflavone genistein. In this study, we show that genistein can induce estrogen-dependent MCF-7 tumor cell growth and increase breast cancer-associated aromatase expression and activity in vitro. We have previously developed an in vitro breast cancer model where the positive feedback loop between primary BAFs and estrogen-dependent MCF-7 tumor cells is operational, thereby representing a more natural in vitro model for breast cancer. In this model, genistein could negate the growth inhibitory action of the aromatase inhibitor fadrozole at physiologically relevant concentrations. These data suggest that soy-based supplements might affect the efficacy of breast cancer treatment with aromatase inhibitors. Considering the high number of breast cancer patients using soy supplements to treat menopausal symptoms, the increasing risk for adverse interactions with breast cancer treatment is of major concern and should be considered with care.
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PMID:Genistein induces breast cancer-associated aromatase and stimulates estrogen-dependent tumor cell growth in in vitro breast cancer model. 2185 27


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