To fully appreciate the complexity of HRT, it is important to understand the various forms of estrogen and their physiological effects. More than 15 forms of natural estrogen have been identified (Taioli, 2010) including estrone, estradiol, and estriol.
Each of these estrogens has particular functions. Estradiol (E2) (the predominant form in non-pregnant, reproductive females) primarily aids in the cyclic release of eggs from the ovaries (i.e., ovulation). E2 has beneficial effects on the heart, bone, brain and colon. Reduction in the level of E2 causes common menopausal symptoms such as hot flashes and night sweats. Estrone (E1), produced in the ovaries and fat cells, is the dominant estrogen in postmenopausal women. Estriol (E3) is secreted in large quantities by the placenta during pregnancy. However, it is a comparatively weak estrogen, and the form of estrogen least associated with hormone-related cancers. In Europe and Japan, E3 is frequently used for HRT (Head 1998; Kano 2002; Moskowitz 2006; Holtor 2009).
The three types of estrogen convert into many metabolites. E1, for example, may convert into three different forms:
Scientists have identified 2-hydroxyestrone as a “good” or chemoprotective estrogen, while 16-alpha-hydroxyestrone and 4-hydroxyestrone have been associated with the development of cancer (Bradlow 1996; Muti 2000). The relationship between 2-hydroxyestrone and 16-alpha-hydroxyestrone is sometimes expressed as the 2:16 ratio (Taioli 2010).
By increasing the ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone, it may be possible to reduce the risk of estrogen-related cancers (Bradlow 1986; Taioli 2010).
3,3’-Diindolylmethane (DIM) and indole-3-carbinole (I3C) (found in cruciferous vegetables) favorably affect estrogen metabolism and help to optimize the 2:16 ratio. A placebo-controlled, double-blind study of women at increased risk for breast cancer found that four weeks of supplementation with I3C promoted favorable changes in the urinary estrogen 2:16 ratio (Wong 1997; Dalessandri 2004).
Estrogen Receptors and a Closer Look at Estriol
As mentioned previously, estriol (E3) is the form of estrogen least associated with cancer. E3’s protective effects become apparent when examining the differing actions that each of the three primary estrogens exerts upon the estrogen receptors. In breast cells there are two distinct classical estrogen receptors that bind estrogens, estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β). In addition, there is one non-classical estrogen receptor, GPR30 (Paruthiyll 2004; Paech 1997; Katzenellenbogen 2000; Nilsson 200; Wang 2010). The binding of estrogen hormones to ER-α promotes breast cell proliferation, which can exacerbate the spread of existing breast cancer. Conversely, the binding and activation of ER-β attenuates breast cell proliferation and thus may slow the development of a cancerous tumor (Helguero 2005; Bardin 2004; Isaksson 2002; Weatherman 2001).
Estrone (E1) and estradiol (E2) preferentially bind to and activate ER-α, thereby explaining the proliferative effects of these two hormones (Zhu 2006; Rich 2002). E3, on the other hand, binds to and activates ER-β (Zhu 2006; Rich 2002). This helps to explain E3’s “anti-estrogenic” activity and led a noted researcher in HRT to state the following: “This unique property of estriol, in contrast to the selective ER [estrogen receptor] alpha binding by other estrogens, imparts to estriol a potential for breast cancer prevention, while other estrogens [estrone and estradiol], would be expected to promote breast cancer… Because of its differing effects on ER alpha and ER beta, we would expect that estriol would be less likely to induce proliferative [potential cancerous growth] changes in breast tissue and to be associated with a reduced risk of breast cancer” (Holtorf 2009).
Moreover, groundbreaking research has revealed that GPR30 mediates proliferation of breast cancer cells independently of ER-α and ER-β. E2 strongly binds to and activates GPR30, driving proliferation. E3, on the other hand, acts as an antagonist of GPR30, though it has a much lower affinity for GPR30 than E2 (Wang 2010; Lappano 2010). Many carcinogenic toxins, including bisphenol A (BPA) and polychlorinated biphenyl’s (PCB’s), promote the growth of breast cancer cells by functioning as agonists of GPR30 (Wang 2010).
The traditional breast cancer drug tamoxifen, which blocks the activity of ER-α and ER-β, fails to suppress the cancer-promoting effects of GPR30. It is by this mechanism that some estrogen-receptor-positive (ER-positive) breast cancers become drug-resistant. In fact, tamoxifen has been shown to stimulate the growth of drug-resistant breast cancer cells via activation of GPR30 (Ignatov 2010).
E3, through its estrogen receptor modulatory capacity, combats the proliferative effects of E1 and E2 (Melamen 1997; Wang 2010). These scientific findings highlight the importance of emphasizing E3 in any bioidentical hormone replacement regimen intended to restore youthful hormone balance and guard against breast cancer development.