Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention

Exposure to estrogens is associated with increased risk of breast and other types of human cancer. Estrogens are converted to metabolites, particularly the catechol estrogen-3,4-quinones (CE-3,4-Q), that can react with DNA to form depurinating adducts. These adducts are released from DNA to generate apurinic sites. Error-prone base excision repair of this damage may lead to the mutations that can initiate breast, prostate and other types of cancer. The reaction of CE-3,4-Q with DNA forms the depurinating adducts 4-hydroxyestrone(estradiol) [4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These two adducts constitute more than 99% of the total DNA adducts formed. Increased levels of these quinones and their reaction with DNA occur when estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of estrogen activating enzymes and/or deficient expression of the deactivating (protective) enzymes. This unbalanced metabolism has been observed in breast biopsy tissue from women with breast cancer, compared to control women. Recently, the depurinating adduct 4-OHE1(E2)-1-N3Ade has been detected in the urine of prostate cancer patients, but not in urine from healthy men. Mutagenesis by CE-3,4-Q has been approached from two different perspectives: one is mutagenic activity in the lacI reporter gene in Fisher 344 rats and the other is study of the reporter Harvey-ras gene in mouse skin and rat mammary gland. A-->G and G-->A mutations have been observed in the mammary tissue of rats implanted with the CE-3,4-Q precursor, 4-OHE2. Mutations have also been observed in the Harvey-ras gene in mouse skin and rat mammary gland within 6-12 h after treatment with E2-3,4-Q, suggesting that these mutations arise by error-prone base excision repair of the apurinic sites generated by the depurinating adducts. Treatment of MCF-10F cells, which are estrogen receptor-alpha-negative immortalized human breast epithelial cells, with E2, 4-OHE2 or 2-OHE2 induces their neoplastic transformation in vitro, even in the presence of the antiestrogen ICI-182,780. This suggests that transformation is independent of the estrogen receptor. The transformed cells exhibit specific mutations in several genes. Poorly differentiated adenocarcinomas develop when aggressively transformed MCF-10F cells are selected and injected into severe combined immune depressed (SCID) mice. These results represent the first in vitro/in vivo model of estrogen-induced carcinogenesis in human breast epithelial cells. In other studies, the development of mammary tumors in estrogen receptor-alpha knockout mice expressing the Wnt-1 oncogene (ERKO/Wnt-1) provides direct evidence that estrogens may cause breast cancer through a genotoxic, non-estrogen receptor-alpha-mediated mechanism. In summary, this evidence strongly indicates that estrogens can become endogenous tumor initiators when CE-3,4-Q react with DNA to form specific depurinating adducts. Initiated cells may be promoted by a number of processes, including hormone receptor stimulated proliferation. These results lay the groundwork for assessing risk and preventing disease.     

Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients

More than two-thirds of breast cancers occur in post-menopausal women, and depend on the estrogens for their proliferation and survival. For the treatment of estrogen-dependent breast cancers, two major treatment options are now available. One is selective estrogen receptor modulator (SERM) such as Tamoxifen and another is aromatase inhibitor such as Anastrozole, Letrozole and Exemestane, which reduce local in situ formation of estrogens. Although these therapies are clinically active for advanced and early breast cancers, de novo and/or acquired resistance to SERM and/or aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of estrogens in the breast tumors is more important than circulating estrogen in plasma for the growth and survival of estrogen-dependent breast cancer in post-menopausal women. The rationale for the importance of local formation of estrogens is based on the following evidences. Estradiol (E2) levels in breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in breast tumors of post-menopausal women are 10–40 times higher than serum level. Biosynthesis of estrogens in breast tumors tissues occurs via two major different routes, one is aromatase pathway and another is steroid-sulfatase (STS) pathway. Whereas many studies has been reported about aromatase inhibitor and its clinical trial results in breast cancer patients, limited information are available regarding to other estrogen regulating enzymes including STS, its role in breast tumors and STS inhibitors. STS is the enzyme that hydrolyses estrone 3-sulfate (E₁S) and dehydroepiandrosterone-sulfate (DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of estrogen-dependent breast tumors. It has been well known that E₁S level are much higher than E2 level both in plasma and tumor of post-menopausal patients. Recent reports show that more than 80% of breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in breast cancer. Taking these findings into consideration, local formation of estrogens could be partially synthesized from large amount of E₁S by STS, which exist in breast cancer. On the other hand, aromatase localizes in stroma and adipocyte surrounding breast cancer. Furthermore, since estrogen formation from E₁S and DHEA-S (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of estrogen-dependent tumor post-SERM and/or aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal breast cancer patients is reviewed as well as STS inhibitor.     

Intracrinology of estrogens and androgens in breast carcinoma

Intratumoral metabolism and synthesis of biologically active steroids such as estradiol and 5-dihydrotestosterone as a result of interactions of various enzymes are considered to play very important roles in the pathogenesis and development of hormone-dependent breast carcinoma. Among these enzymes involved in estrogen metabolism, intratumoral aromatase play an important role in converting androgens to estrogens in situ from serum and serving as the source of estrogens, especially in postmenopausal patients with breast carcinoma. However, other enzymes such as 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes, estrogen sulfatase (STS), and estrogen sulfotransferase, which contribute to in situ availability of biologically active estrogens, also play pivotal roles in this intratumoral estrogen production above. Androgen action on human breast carcinoma has not been well-studied but are considered important not only in hormonal regulation but also other biological features of carcinoma cells. Intracrine mechanisms also play important roles in androgen actions on human breast carcinoma cells. Among the enzymes involved in biologically active androgen metabolism and/or synthesis, both 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; conversion from circulating androstenedione to testosterone) and 5-reductase (5Red; reduction of testosterone to DHT (5-dihydrotestosterone) were expressed in breast carcinoma tissues, and in situ production of DHT has been proposed in human breast cancer tissues. However, intracrine mechanisms of androgens as well as their biological or clinical significance in the patients with breast cancer have not been fully elucidated in contrast to those in estrogens.     

17 beta-hydroxysteroid dehydrogenases and cancers

17β-Hydroxysteroid dehydrogenases (17HSDs) catalyze the interconversions between active 17β-hydroxysteroids and less-active 17-ketosteroids thereby affecting the availability of biologically active estrogens and androgens in a variety of tissues. The enzymes have different enzymatic properties and characteristic cell-specific expression patterns, suggesting differential physiological functions for the enzymes. Epidemiological and endocrine evidence indicate that estrogens play a key role in the etiology of breast cancer while androgens are involved in mechanisms controlling the growth of prostatic cells, both normal and malignant. Recently, we have developed, using LNCaP prostate cancer cell lines, a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition to more aggressive cells, able to grow in suspension cultures. Our results suggest that substantial changes in androgen and estrogen metabolism occur in the cells during the process. These changes lead to increased production of active estrogens during transformation of the cells. Data from studies of breast cell lines and tissues suggest that the oxidative 17HSD type 2 may predominate in human non-malignant breast epithelial cells, while the reductive 17HSD type 1 activity prevails in malignant cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach to treat estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered as estrogen target tissues such as colon. Our data show that the abundant expression of 17HSD type 2 present in normal colonic mucosa is significantly decreased during colon cancer development.     

Risk of breast cancer with progestins: critical assessment of current data

Whether progestins protect against the risk of breast cancer or enhance that risk has been a major area of controversy over the past several years. Observational studies have reported conflicting results and experimental studies examining whether progestins exert mitogenic or anti-mitogenic actions on breast tissue report divergent results. Based upon a wide range of animal, epidemiologic and clinical data, most investigators agree that estrogens contribute to the development of breast neoplasms. However, the additional effect of progestins on this risk has been the subject of substantial discussion and controversy. A variety of experiments have been carried out using human breast cancer cells grown in vitro and as xenografts in nude mice. These studies demonstrated both mitogenic and anti-mitogenic effects depending upon the precise experimental conditions. Two potential reasons for these differences include differential metabolism of progestins into inhibitory pregnenes or stimulatory 5-alpha-reduced pregnanes or the presence of a protein (GPR 30) which allows the anti-mitogenic effects of progestins to be manifest. Based upon the conflicting nature of the results in experimental studies, we believe that only data in patients provide substantial insight into the actions of progestins on the intact human breast. Studies have now demonstrated that cell proliferation and breast density is higher during the luteal than during the follicular phase of the menstrual cycle. In postmenopausal women, long-term exposure to estrogen plus a progestin results in a marked enhancement of proliferation of the terminal duct lobular units as well as in breast density. These data, taken together, provide substantial evidence that progestins are mitogenic on the human breast when given long term to postmenopausal women. To critically evaluate the observational studies regarding breast cancer risk from progestins, we developed a set of stringent criteria for acceptance of individual studies. Four of the five studies meeting these criteria reported a greater risk of breast cancer with combination estrogen/progestin regimens than with estrogen alone. More importantly, the first randomized, prospective, controlled trial of the risk of breast cancer with an estrogen/progestin combination (the Women's Health Initiative Study) has now been published. This study reported a 26% increased relative risk of breast cancer with the estrogen/progestin combination. Based upon these data, we believe that progestins do add to the risk of breast cancer over and above that imparted by estrogen alone. The attributable risk during use for 5 years or less is small but increases logarithmically during long-term use. The majority of data regarding progestins are derived from regimens using MPA. However, we conclude from our analysis that the burden of proof regarding progestins has now shifted. One must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful.     

Analysis of estrogens in serum and plasma from postmenopausal women: Past present,and future

Previous studies have shown that the selection of women who are at high breast cancer risk for treatment with chemoprevention agents leads to an enhanced benefit/risk ratio. However, further efforts to implement this strategy will require the development of new models to predict the breast cancer risk of particular individuals. Postmenopausal women with elevated plasma or serum estrogens are at increased risk for breast cancer. Therefore, the roles of various enzymes involved in the biosynthesis of estrogens in postmenopausal women have been reviewed in detail. In addition, the potential genotoxic and/or proliferative effects of the different estrogen metabolites as risk factors in the etiology of breast cancer have been examined. Unfortunately, much of the current bioanalytical methodology employed for the analysis of plasma and serum estrogens has proved to be problematic. Major advances in risk assessment would be possible if reliable methodology were available to quantify estradiol and its major metabolites in the plasma or serum of postmenopausal women. High performance liquid chromatography (HPLC) coupled with radioimmunoassay (RIA) currently provides the most sensitive and best validated immunoassay method for the analysis of estrone and estradiol in serum samples from postmenopausal women. However, inter-individual differences in specificity observed with many other immunoassays have caused significant problems when interpreting epidemiologic studies of breast cancer. It is almost impossible to overcome the inherent assay problems involved in using RIA-based methodology, particularly for multiple estrogens. For reliable measurements of multiple estrogens in plasma or serum, it will be necessary to employ stable isotope dilution methodology in combination with liquid chromatography–tandem mass spectrometry (LC–MS/MS). Extremely high sensitivity can be obtained with pre-ionized estrogen derivatives when employed in combination with a modern triple quadrupole mass spectrometer and nanoflow LC. Using [¹³C₆]-estrone as the internal standard it has proved possible to analyze estrone as its pre-ionized Girard T (GT) derivative in sub-fg (low amol) amounts on column. This suggests that in the future it will be possible to routinely conduct LC–MS assays of multiple estrogen metabolites in serum and plasma at even lower concentrations than the current lower limit of quantitation of 0.4 pg/mL (1.6 pmol/L). The ease with which the pre-ionization derivatization strategy can be implemented will make it possible to readily introduce high sensitivity stable isotope dilution methodology in laboratories that are currently employing LC–MS/MS methodology. This will help conserve important plasma and serum samples as it will be possible to conduct high sensitivity analyses using low sample volumes.     

Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk

Multiple lines of evidence support a central role of hormones in the etiology of breast cancer. In epidemiologic studies, considerable effort has focused on delineating the role of endogenous hormones in risk of breast cancer among postmenopausal women. Recently, substantial additional data has accrued from prospective studies where endogenous hormones are measured in study subjects prior to disease diagnosis. In this review, the epidemiologic evidence linking sex steroids—estrogens, testosterone, and progesterone, specifically—with subsequent risk of breast cancer in both premenopausal and postmenopausal women is summarized. Overall, a strong positive association between breast cancer risk and circulating levels of both estrogens and testosterone has now been well confirmed among postmenopausal women; women with hormone levels in the top 20% of the distribution (versus bottom 20%) have a two- to three-fold higher risk of breast cancer. Evidence among premenopausal women is more limited, though increased risk associated with higher levels of testosterone is consistent. However, both positive and null associations have been observed with estrogens and progesterone and clearly more evaluation is needed.     

Enterolactone and estradiol inhibit each other''s proliferative effect on MCF-7 breast cancer cells in culture

In earlier studies it has been shown that women with breast cancer and at risk for breast cancer have low excretion of urinary mammalian lignans (enterolactone and enterodiol) mainly due to low intake of whole-grain products and other fiber-rich foods. It is well known that estradiol (E2) has proliferative effects on estrogen dependent cancer cells and that antiestrogens inhibit this effect. To elucidate whether enterolactone (Enl) has antiestrogenic properties we studied, using MCF-7 breast cancer cells in culture, the in vitro effect of relatively low concentrations of Enl added both alone and in combination with E2. E2 (1 nmol/l) and Enl (0.5–2 μmol/l) separately stimulated the proliferation of MCF-7 cells, but their combination always resulted in lower stimulation than any of them alone, or the combined compounds had no stimulatory effect at all compared to the control. Higher concentrations above 10 μmol/l of Enl inhibited significantly the growth of the cells suggesting a toxic effect. The lignan was very rapidly conjugated to its monosulfate. It is suggested that one possible mechanism by which Enl may affect the growth of these estrogen sensitive cells is by competition of Enl and its sulfate with the estrogens for sulfokinases and sulfatases involved in estrogen metabolism in the cells. It is concluded that Enl inhibits E2-stimulated MCF-7 breast cancer cell growth in vitro, and vice versa. The concentrations of Enl needed for the elimination of the proliferative effect of E2 are physiologic and similar to those used in corresponding experiments utilizing tamoxifen.     

Aromatase inhibitors: assessment of biochemical efficacy measured by total body aromatase inhibition and tissue estrogen suppression

The implementation of aromatase inhibitors for treatment of early and metastatic breast cancer has been one of the major improvements in endocrine therapy of breast cancer. Measurement of endocrine effects of aromatase inhibition in vivo has been a major tool in the process of evaluating novel compounds. Biochemical efficacy of aromatase inhibitors in vivo may be determined from their effects on “total body aromatization” as well changes in plasma and tissue estrogen levels. Due to high sensitivity, tracer methods allowing calculation of whole body aromatase inhibition are still considered the gold standard. The method developed by our group in collaboration with the Royal Marsden Hospital and the results of this joint program are summarized and discussed. These studies allowed classification of the different aromatase inhibitors and their optimal dosage, selecting the best compounds for clinical evaluation. In vivo total body aromatase assessment is a work-consuming method, allowing such studies to be conducted in a limited number of patients only. In contrast, plasma estrogen measurement is a cruder but simpler method, allowing screening of larger groups of patients. As plasma estrogens arise through passive diffusion of estrogens synthesized in different body compartments, plasma estrogens, as well as total body aromatase assessment, present a rough estimate of total body tissue estrogen production, and changes associated with treatment with aromatase inhibitors reflect the effects on tissue estrogen production in general. However, plasma estrogen levels do not correlate to breast cancer tissue estrogen levels. This is due to the endocrine autonomy of breast cancer tissue with significant local estrogen production in some tumors. Thus, direct measurement of intratumor estrogens is demanded to evaluate the effects of aromatase inhibitors in malignant target tissues. Our group has developed a highly sensitive HPLC-RIA for the simultaneous measurement of estrone, estradiol, and estrone sulfate in malignant breast tissue samples, and we are currently using this method to assess alterations in intratumor estrogen levels during treatment with different aromatase inhibitors.     

Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer

Objective

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

October 2001.Hormone replacement therapy (HRT) connotes treatment with either estrogen alone or estrogen with progesterone in postmenopausal women. Menopausal symptoms, such as hot flashes and vaginal dryness, and the potential long-term effects of estrogen deprivation are a concern to women with breast cancer, particularly those in whom menopause develops early as a result of adjuvant chemotherapy.Traditionally, the use of HRT has been contraindicated in women with breast cancer because of the notion that the development and growth of breast cancer is estrogen dependent and that the introduction of HRT may increase the risk of breast cancer recurrence. The focus of this guideline is on whether it is safe to give HRT to women with breast cancer.     

Physiological and pharmacological effects of estrogens in breast cancer.

Focus here is on the mechanism of action of both estrogens and antiestrogens at the tumor cell levels in breast cancer. The interactions of estrogens and their antagonists are emphasized and analyzed in terms of current and potential clinical applications to breast cancer treatment. This review deals with these interrelationships at the molecular levels, not just with general aspects of endocrine interrelationships. The article is divided into 8 main parts: 1) an introduction, which reviews historical understanding of receptor technology and significances; 2) main properties of estrogens and estrogen receptors; 3) the influence of estrogens and antiestrogens on growth of experimental mammary tumor systems; 4) the suppression of or administration of estrogens for treatment of advanced human breast cancer; 5) estrogen receptivity of mammary tumors; 6) progress in treatment of advanced breast cancer derived from studies on the mode of action of estrogens; 7) the prognostic significance of estrogens and estrogenic receptivity (the estriol theory); and 8) concluding remarks on the future paths of receptor research.     

Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators

Despite the dramatic fall in plasma estrogen levels at menopause, only minor differences in breast tissue estrogen levels have been reported comparing pre- and postmenopausal women. Thus, postmenopausal breast tissue has the ability to maintain concentrations of estrone (E₁) and estradiol (E₂) that are 2–10- and 10–20-fold higher than the corresponding plasma estrogen levels. This finding may be explained by uptake of estrogens from the circulation and/or local estrogen production. Local aromatase activity in breast tissue seems to be of crucial importance for the local estrogen production in some patients while uptake from the circulation may be more important in other patients. Beside aromatase, breast tissue expresses estrogen sulfotransferase and sulfatase as well as dehydrogenase activity, allowing estrogen storage and release in the cells as well as conversions between estrone and estradiol. The activity of the enzyme network in breast cancer tissue is modified by a variety of factors like growth factors and cytokines. Aromatase inhibitors have been used for more than two decades in the treatment of postmenopausal metastatic breast cancer and are currently investigated in the adjuvant treatment and even prevention of breast cancer. Novel aromatase inhibitors and inactivators have been shown to suppress plasma estrogen levels effectively in postmenopausal breast cancer patients. However, knowledge about the influence of these drugs on estrogen levels in breast cancer tissue is limited. Using a novel HPLC-RIA method developed for the determination of breast tissue estrogen concentrations, we measured tissue E₁, E₂ and estrone sulfate (E₁S) levels in postmenopausal breast cancer patients before and during treatment with anastrozole. Our findings revealed high breast tumor tissue estrogen concentrations that were effectively decreased by anastrozole. While E₁S was the dominating estrogen fraction in the plasma, estradiol was the estrogen fraction with the highest concentration in tumor tissue. Moreover, plasma estrogen levels did not correlate with tissue estrogen concentrations. The overall experience with aromatase inhibitors and inactivators concerning their influences on breast tissue estrogen concentrations is summarized.     

Aromatase inhibitors and their application in breast cancer treatment*

Estrogens are known to be important in the growth of breast cancers in both pre- and postmenopausal women. The number of breast cancer patients with hormone-dependent disease increases with age, as does the incidence of breast cancer. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. Because aromatase catalyzes the rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme have been developed in the last few years as a logical treatment strategy. Two classes of aromatase inhibitors, steroidal and nonsteroidal compounds, are now in use. Among the steroid substrate analogs, formestane and examestane have been shown to be effective in breast cancer patients with advanced disease. Highly potent and selective nonsteroidal inhibitors have recently been found to suppress plasma and urinary estrogens by more than 95% in breast cancer patients. Two of these compounds recently were approved in the United States and have been shown to be more effective than other second-line agents in terms of overall response rates and treatment failure, as well as better tolerated. Although studies of the efficacy of these agents in earlier stage disease are awaited, it is evident that aromatase inhibitors can extend the duration of treatment in breast cancer patients.     

Estrogens, progestins, and coronary artery reactivity in atherosclerotic monkeys

It has been known for many years that sex hormones modulate vasodilator responses of arteries supplying the uterus with blood. Recently, it has been shown that sex hormones such as estrogen modulate vasomotor responses of other arteries, including coronary arteries. It is thought that modulation of vasodilator and constrictor responses of coronary arteries may be one mechanism by which estrogen affects the risk of coronary heart disease. Although several studies have examined the effects (and potential mechanisms) of estrogen on vasodilator responses of nonatherosclerotic arteries, few have focused on estrogen's effects on atherosclerotic coronary arteries. In studies of ovariectomized atherosclerotic female cynomolgus monkeys, both long-term (2 years) and short-term (20 min) estradiol treatment augments dilator responses to acetylcholine, but not nitroglycerin. Presumably, this indicates an effect of estradiol on endothelium-mediated dilator responses of coronary arteries. Addition of the progestin medroxyprogesterone acetate diminishes the beneficial effect of conjugated equine estrogens on these dilator responses. This is significant because a progestin is usually added to estrogen replacement to reduce the risk of endometrial and breast cancer associated with unopposed estrogen therapy. However, it would seem that not all progestins act similarly on vascular reactivity. Studies in monkeys indicate that addition of progesterone or the progestin medroxyprogesterone acetate does not diminish the beneficial effects of estrogen on coronary dilator responses. Thus it would appear that different estrogen/progestin combinations may affect vascular reactivity in different manners, There is also an effort being made to examine the potential of different kinds of estrogens on cardiovascular risk. Studies in monkeys indicate that one of the estrogens found in conjugated equine estrogens (17 alpha-dihydroequilenin) has estrogen effects on vascular reactivity without having detrimental effects on uterine pathology. The isoflavones “plant estrogens” found in soy protein also have estrogenic effects on vascular reactivity and inhibition.     

Estrogenic plant extracts reverse weight gain and fat accumulation without causing mammary gland or uterine proliferation

Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women.     

Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer

Inhibition of postmenopausal estrogen production by aromatase inhibitors is an established drug treatment modality for postmenopausal breast cancer. In this article postmenopausal estrogen disposition and the alterations caused by treatment with aromatase inhibitors are reviewed. Recent investigations have challenged the hypothesis that aromatization of androstenedione into estrone is the sole production pathway for estrogens in postmenopausal women. The finding that estrogens persist in the plasma of patients receiving aminoglutethimide treatment despite a near total inhibition of the aromatase enzyme suggests that alternative pathways for estrogen synthesis exist. While nonspecific actions of aromatase inhibitors may be disadvantageous, certain effects may also be beneficial. Recent findings that aminoglutethimide may induce estrone sulfate metabolism questions whether this "prototype" aromatase inhibitor might have a dual mechanism of action. The importance of investigating the possible influence of different aromatase inhibitors on all components of estrogen disposition is considered.