Attached is an article that is very detailed explaining the risk of breast cancer depending on the type of hormone replacement therapy used. In a quick summary, in this study when estrogen is used alone the risk of breast cancer increases to 1.3 with normal being 1.00. This differs from the Women’s Health Initiative Study in which conjugated estrogen alone showed no increased risk and actually slightly lower risk of breast cancer. However, usually when estrogen is given a type of progestagen is given along with the estrogen especially in women who still have a uterus. And this is the key: Which type of progestagen is used with estrogen.
When estrogen is used with a synthetic progestagen (the most commonly used in the USA is Provera or medroxyprogesterone) the incidence of breast cancer rises dramatically. The risk rises to 1.69 with 1.00 being normal. If estrogen is used with the natural progestagen (progesterone as seen in the normally functioning female during menstruating years) the risk is 1.00, equal to non-uses of HRT.
At our clinic, natural estradiol and natural progesterone are used, never the synthetic.
The article is very long. There are large portions that are deleted as they are technical and may not add to what can be gained by reading all the details. However, the article in its entirety can be found on the internet.
Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study
Agnès Fournier, Franco Berrino, and Françoise Clavel-Chapelon, E3N, Nutrition, hormones et cancer: épidémiologie et prévention, Université Paris Sud – Paris XI, EA4045, Institut Gustave-Roussy, Department of Preventive and Predictive Medicine Istituto Nazionale Tumori, Milan,IT
Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02–1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83–1.22) for estrogen–progesterone, 1.16 (0.94–1.43) for estrogen–dydrogesterone, and 1.69 (1.50–1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.
Estrogen–progestagen postmenopausal hormone replacement therapy (HRT) has been classified as carcinogenic to humans with respect to breast cancer, on the basis of both observational studies and randomized controlled trials . However, small structural changes in progestagens may considerably alter their effects [2, 3]. The relationship between estrogen-only therapy and breast cancer risk is also the subject of intense debate: unopposed estrogen use was associated with a decreased risk of breast cancer in the Women’s Health Initiative (WHI) trial , but not in some observational studies [7–14].
Millions of women are still using HRTs, as estrogen remains the most effective treatment to alleviate menopausal symptoms . It is therefore crucial to evaluate the effect of different HRTs on breast cancer risk and identify the safest preparations.
In France, estrogen, mostly estradiol administered through the skin, is used alone or combined with a variety of progestagens. Further to our earlier report (2005), in which we discussed the breast cancer risk associated with three broad categories of HRTs (estrogens alone, combined with progesterone, or with synthetic progestins) , we now report on the association between various other HRTs and breast cancer risk in 80,377 postmenopausal women after up to 12 years of follow-up. In what follows, “other progestagens” should be understood to mean “progestagens other than progesterone and dydrogesterone”.
Compared with women who had never used HRT, women in the estrogen alone and estrogen–other progestagens groups had a significantly increased breast cancer risk (relative risks 1.29 (95% confidence interval 1.02–1.65), and 1.69 (1.50–1.91), respectively). Estrogen-progesterone was associated with a relative risk of 1.00 (0.83–1.22), and estrogen–dydrogesterone with a relative risk of 1.16 (0.94–1.43). Estrogen alone, estrogen–progesterone and estrogen–dydrogesterone were associated with breast cancer risks that did not differ significantly from one another, but that were all significantly lower than that of estrogen–other progestagens (P for homogeneity 0.03, <0.001, and <0.001, respectively). There were significant trends of increased risk with increased duration of use of estrogen–progesterone and estrogen–other progestagens. However, even short spells of estrogen–other progestagens use (<2 years) were associated with a significant 1.36-fold increase in breast cancer risk.
When analyses were restricted to women with the most accurate age at menopause (i.e., derived from information on age at last menstrual period—unless due to hysterectomy, and/or self-reported age at menopause), our main conclusions remained unchanged. This sensitivity analysis yielded relative risks of 1.2, 1.0, 1.2, and 1.6 for estrogen alone, estrogen–progesterone, estrogen–dydrogesterone, and estrogen–other progestagens, respectively, compared with HRT never-use.
We found that the risk of invasive breast cancer was significantly lower with estrogen–progestagen HRTs containing progesterone or dydrogesterone than with HRTs containing other progestagens. The latter group involved a variety of progestins whose associations with breast cancer risk did not differ significantly from one another. We also observed a significantly increased risk of breast cancer with the use of estrogen alone.
The effect of progestagens on breast tissue is complex and not completely understood. The mechanisms by which they act on cell proliferation include interaction with steroid receptors, growth factors and oncogenes, and with the cell-cycle and estrogen metabolizing enzymes . Because progestagens differ widely in their chemical structure, metabolism, pharmacokinetics and potency, it is reasonable to expect them to induce different responses in the breast .
Recently, Wood et al.  compared the effects of estradiol given with either medroxyprogesterone acetate or micronized progesterone on risk biomarkers for breast cancer in a postmenopausal primate model. In this randomized crossover trial, they found that, compared to placebo, estradiol + medroxyprogesterone acetate resulted in significantly greater proliferation (as measured by Ki67 expression) in lobular and ductal breast epithelium, while estradiol + micronized progesterone did not. This result supports our findings suggesting that, when combined with an estrogen, progesterone may have a safer risk profile in the breast compared with some other progestagens.
The high degree of androgenicity of progestins used in certain HRTs has been hypothesized to play a role in the increased risk of breast cancer . Our results do not support this hypothesis, as, when combined with an estrogen, neither promegestone, nomegestrol acetate, chlormadinone acetate or medrogestone (all nonandrogenic progestagens) nor cyproterone acetate (an antiandrogenic progestagen) had effects that differed significantly from that of norethisterone acetate (the most androgenic progestagen cited). These results are in line with those of two other European studies [10, 11], which found no difference between the effect of 19-nortestosterone derivatives and medroxyprogesterone acetate (a 17-hydroxyprogesterone derivative with lower androgenic potential than 19-nortestosterone derivatives), implying that other parameters must be involved. However, possible preferential prescribing of the nonandrogenic or antiandrogenic HRTs to women with signs of insulin resistance or hyperandrogenism, who are at higher risk of breast cancer , could partly explain our findings.
In our study, estrogen alone was associated with a significantly lower increase in breast cancer risk than estrogen opposed with a progestagen (with the exception of progesterone or dydrogesterone), in line with the growing evidence that adding certain progestins to estrogen has an adverse impact on breast cancer risk . However, our finding of a 1.3-fold increased breast cancer risk associated with the use of estrogen alone (almost exclusively estradiol compounds, and mostly administered through the skin) differs with that of the WHI estrogen-alone trial which found a decreased risk when oral conjugated equine estrogens were used in a population of older and often overweight women .
E3N is the first epidemiological study that we know of to be providing results indicating that estrogen–progesterone and estrogen–dydrogesterone combinations may be the least harmful estrogen–progestagen HRTs regarding breast cancer risk. However, more evidence is required before these results can be translated into firm clinical recommendations for the management of menopausal symptoms. In addition, the effect of these combinations in other diseases (e.g., coronary heart disease, venous thromboembolism and colorectal cancer) has also to be evaluated.
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