The importance of Estriol as it relates to lessened breast cancer risk. Also the mechanism of estriol being a prime stimulant of estrogen receptor site beta, the deproliferative step in breast glandular cell cycling.
1 The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy? Kent Holtorf MD. Postgrad Med 2009;121(1):1-13.
Abstract: Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective. Objective: This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease. Methods: Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected. Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animalderived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.
2a Comparative Measurements of Serum Estriol, Estradiol, and Estrone in Non-pregnant, Premenopausal Women: A Preliminary Investigation by Jonathan V. Wright, MD Altern Med Rev 1999;4(4):266-270.)
Abstract” Little to no data exists in the literature for serum estriol values in non-pregnant, premenopausal women. The current medical community opinion holds that estriol has no significant role in non-pregnant women relative to the other estrogens. It is a possibility that estriol’s primary function has yet to be discovered. Accordingly, the first step is to understand cycle-dependent serum estriol concentrations. We have made a preliminary investigation of serum estriol concentration in 26 women during the known cycle peaks of estrone and estradiol. Five of the women were also tested for serum estriol on various days throughout the cycle in order to develop a cycle-dependent concentration profile. The result of these experiments show that serum estriol was always significantly higher than the sum of estrone and estradiol and less fluctuating. We conclude that estriol is probably a significant estrogen component.
2b Morphological Changes in Breast Tissue with Menstrual Cycle. Rathi Ramakrishnan, M.D. Mod Pathol. 2002 Dec;15(12):1348-56.
Abstract: Whether the breast tissue undergoes morphologic changes in relation to the menstrual cycle had been a subject of debate. Elegant studies performed in the early 1980s provided conclusive evidence of cyclical changes in the normal breast lobules. These studies were almost entirely based on autopsy material and have not been validated in the clinical setting. In the present study, we examine breast tissues from surgical specimens from 73 premenopausal women and use morphological criteria to characterize the stage of the menstrual cycle. Patients taking oral contraceptives or hormonal therapy were excluded from this study. The following histological parameters were used to assess the menstrual stage: number of cell layers in the acini and presence and degree of vacuolation of the myoepithelial cells, stromal edema, infiltrate, mitosis, and apoptosis. The morphological stage was then correlated with the stage of the cycle, as determined by last menstrual period and the usual menstrual cycle length and in some patients with serum estrogen and progesterone levels. The morphologic stage was concordant with dates in 54 of the 73 patients (74%, P =.001). In 31 of these patients, serum levels of estradiol and progesterone at the time of surgery were available for correlation. Twenty-five (80%) of these were phase concordant by morphology and progesterone levels (P =.01), and 25 (80%), by dates and progesterone levels (P =.007). Women with a high morphologic score were seven times as likely to be in luteal phase as were women with a low score (odds ratio, 7.1; 95% confidence interval). Menstrual phase can be determined by the morphology of the normal lobules present within the surgically excised breast specimens. This will permit retrospective analysis of large archival databases to analyze the effect of timing of surgery in relation to menstrual cycle phase. It will also aid the design of epidemiological studies for breast cancer risk assessment.
2c Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. Author: Lemon HM; Wotiz HH; Parsons L; Mozden PJ. Journal of the American Medical Association. June 27, 1966; 196(13):112-120.
Abstract: 24-hour urinary estriol excretion quotients (Eq) was measured in a group of 148 collections of 64 breast cancer or precancer patients (182 specimens) and 34 controlled abnormally menstruating young women without breast cancer, normally menstruating women free of cancer and from healthy and diseased postmenopausal women without breast cancer at University Hospital in Boston. As an index of the ratio of non-carcinogenic impeded estrogens to mammary carcinogenic estrogens, there was some tendency to select urines from patients early in the disease. An attempt was made when frozen urines were analyzed to select control and cancerous specimens that had been frozen for equivalent time periods. Based on literature studies, .7 was considered the low normal Eq limit in premenopausal women and 1.0 for postmenopausal or post castration women. No major differences in Eq were noted from the proliferative and the secretory phases of the menstrual cycle. 2 of the normally menstruating control women showed subnormal Eq and 1 had an excessively high Eq. Single analyses from the postmenopausal showed a mean Eq of 3.2. Previously oopherectomized women had mean values of 7.8 and 3 patients with well-compensated cardiovascular disease had Eq’s of 5.4 to 8.8. 3 patients with premalignant breast or uterine pathology had subnormal Eq value. Oopherectomized women with recurrent breast cancer had lower Eq values than the oopherectomized controls. Pre-and postmenopausal patients with proven breast cancer excreted 30-60% less estriol per 24 hours than the control population. The daily excretion of estione and estradiol was similar in both groups. 24 controls and patients matched in pairs by age and ovarian status in the Wilcoxon test indicated that the decreased Eq excretion in untreated cancer was significant at the 2% level. Endocrine therapy led to a rise in Eq. Major breast or abdominal surgery led to an increased Eq. It is suggested that a disproportionately large number of subnormal estriol excretors may develop precancerous or malignant tumors.
2d The role of estrogen receptor beta (ERbeta) in malignant diseases–a new potential target for antiproliferative drugs in prevention and treatment of cancer. Warner M, Gustafsson JA.Biochem Biophys Res Commun. 2010 May 21;396(1):63-6. Center for BioSciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Abstract: The discovery of ERbeta in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ERalpha, but by two balancing factors, ERalpha and ERbeta, which are often antagonistic to one another. Excitingly, ERbeta has been shown to be widespread in the body and to be involved in a multitude of physiological and pathophysiological events. This has led to strong interest in the pharmaceutical industry to target ERbeta by drugs against various diseases. In this review, the focus is on the role of ERbeta in malignant diseases where the anti-proliferative activity of ERbeta gives hope for new therapeutic approaches.
2e Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding. Bao Ting Zhu, Gui-Zhen Han, Joong-Youn Shim, Yujing Wen and Xiang-Rong Jiang Department of Basic Pharmaceutical Sciences, College of Pharmacy (B.T.Z., G.-Z.H., Y.W., X.-R.J.), University of South Carolina, Columbia, South Carolina 29208; and Julius L. Chambers
Abstract: To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) α or β subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17β (E2) and estrone (E1) for human ERα and ERβ. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ERα and ERβ, but some of them retained a differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16α-hydroxyestradiol (estriol), 16β-hydroxyestradiol-17α, and 16-ketoestrone, had a distinct preferential binding affinity for human ERβ over ERα (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ERα and ERβ, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ERα over ERβ, whereas 16α-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ERβ over ERα. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ERα or ERβ signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ERα and ERβ yielded useful information on the structural features that determine the preferential activation of the ERα and ERβ subtypes, which may aid in the rational design of selective ligands for each human ER subtype.
2f Differential Regulation of Estrogen Receptor (ER)α and ERβ in Primate Mammary Gland. Guojun Cheng Yan Li Yoko Omoto Yanling Wang Tove Berg Magnus Nord Pirkko Vihko Margaret Warner Yun-Shang Piao Jan-Åke Gustafsson. The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 1, 1 January 2005, Pages 435–444,
Abstract: Estrogen, mainly estradiol (E2), and progesterone (P) are essential for the growth and differentiation of the breast, but their roles in breast cancer are highly debated. To understand how E2 and P influence cell proliferation and differentiation, it is essential to know how their receptors are regulated. Because of limited tissue availability, little is known about the regulation of the two estrogen receptors (ERα and ERβ) and the two progesterone receptor isoforms (PR-A and PR-B) in the normal human breast. What we know comes from rodent studies, which are not always pertinent for the human breast. We report now on the regulation of gonadal hormone receptors during the menstrual cycle, pregnancy, and lactation in the rhesus monkey mammary gland and on the relationship of these receptors to proliferation. We found that ERα but not ERβ is down-regulated when E2 levels increase and when cells enter the cell cycle. PR-B but not PR-A is expressed in proliferating cells. Thus under normal conditions, the ratio of ERα to ERβ in the breast depends on plasma concentrations of E2. Elevated expression of ERα (as occurs in postmenopausal women) is a normal response to the loss of E2 and indicates nonproliferating cells. As selective receptor ligands become available, they will be helpful in the delineation of the functions of these receptors.
2g Loss of ERβ expression as a common step in estrogen-dependent tumor progression Allison Bardin,1 Nathalie Boulle,2,1 Gwendal Lazennec,1,* Françoise Vignon,1 and Pascal Pujol2,1,*Endocr Relat Cancer. 2008 Feb 4.
Abstract: The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues and the mitogenic effects of estrogen in these tissues (e.g. breast, endometrium, and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these issues, most studies have shown decreased ERβ expression in cancer as compared to benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ or ERβ specific gene induction could indicate that ERβ has a differential effect on proliferation as compared to ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, e.g. via ligand-specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.
2h Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential.Ilaria Paterni,a Carlotta Granchi,a, John A. Katzenellenbogen, b and Filippo MinutoloaSteroids. 2014 Nov 15; 0: 13–29.
Abstract: Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for the prevention and treatment of a wide variety of pathological conditions, such as cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications.