Continuing my own analysis of the IMS comment (in bold) on the study:
The authors have tried to minimise bias in their analyses, but it is important to recognise that observational studies include unquantifiable confounding effects, for which corrections cannot be made, and so as in all studies, there are limitations.Correct. The authors have tried to minimize bias using the available current tools to achieve that.
Correct: all studies have limitations.
It is extremely important to note that this paper does not inform us of the impact of current recommended MHT prescribing practices on breast cancer risk.It's quite difficult to quantify the impact of current MHT prescribing practices on BC risk, for the obvious fact that BC takes time to develop and the ‘current recommended MHT prescribing practices' are only going to show (or not) increased BC risks over time.
With an average use of 10 years of MHT in current users at diagnosis, and 7 years in past users, much of the exposure to MHT preceded the first publication of the Women's Health Initiative study, after which prescribing practices changed substantially. Consequently, virtually all of the included information pertains to MHT formulations and doses known to have adverse breast effects that are no longer recommended. Specifically, the use of the progestogens medroxyprogesterone acetate and norethisterone (norethindrone) is now discouraged because of their known adverse effects, but these account for nearly all of the data for combined estrogen-progestogen therapy included in the paper.I had no idea norethisterone is no longer recommended and now discouraged. (!)
Additionally, the majority of cases were women who took oral estrogen, which results in high blood levels of the hormone estrone, whereas transdermal therapy does not (2). Estrone is not only the main estrogen produced by postmenopausal women, but levels are higher in overweight/obese women, such that estrone may be a key factor linking obesity with breast cancer.I'd like to see references for these affirmations.
Estrone is the main oestrogen produced by postmenopausal women, but this is a normal shift in the metabolism of oestrogens, also seen during pregnancy, when estriol rises. Nature is wise, older women with lots of cell genetic mutations (including oocytes) should not have increaed risks of cell multiplication by mitogenic estradiol, thus estrone and not estradiol, which main function lies in reproduction, takes over.
Estrone is reversibly converted to estradiol through the action of 17β-hydroxysteroid dehydrogenase enzyme in peripheral tissues, so it's not easy to separate the potential roles of estrone and estradiol in BC.
https://cancerres.aacrjournals.org/content/79/13_Supplement/590.short‘A number of known breast cancer risk factors have been proposed to influence risk via effects on estrogens. Obesity, defined as BMI> 30 kg/m2, raises the risk of postmenopausal breast cancer, and this has been attributed to the higher circulating levels of estrogens synthesized in the adipose tissue of obese women. At the same time, an inverse association between obesity and SHBG blood levels has been reported, which in turn, contributes to higher concentrations of free estradiol (bioavailable fraction) in the circulation.
The magnitude of the associations of estrogens with a number of breast cancer risk factors including obesity, reproductive, demographic, and life style factors has been investigated by the Endogenous Hormones and Breast Cancer Collaborative Group in several studies. In a pooled analysis of eight prospective studies in postmenopausal women, adjusting data for free estradiol concentrations attenuated breast cancer risk by 17% for each 5 kg/m2 increase in BMI, resulting in a loss of statistical significance for the association between BMI and breast cancer risk [104]. In another cross-sectional analysis of 13 prospective studies by the same group, estrogen and androgen levels were positively associated with obesity, smoking (15+ cigarettes daily) and alcohol consumption (20+g alcohol daily), and inversely linked with age. By contrast, SHBG concentrations were greater in older women and lower in obese women and those consuming alcohol [105].'
‘The association between circulating endogenous estrogens and breast cancer risk in postmenopausal women has been conclusively established, and compelling evidence exists to support a causal relationship. Epidemiological studies have consistently shown a 2–3 fold increase in breast cancer risk in women with elevated blood estradiol levels. On the other hand, findings from estrogen metabolite investigations are mixed. This inconsistency in estrogen metabolite results may be due to methodological differences in participant characteristics, study design and follow-up length (for some studies insufficient), number of cases (some studies under-powered), and high inter-individual variation in serum and urinary concentrations of estrogen metabolites, or limitations associated with estrogen metabolite measurement. Of particular note are differences in assay methodologies. Until recently, the leading methodology for measurement of estrogen metabolites was ELISA, a method that has limited specificity and sensitivity. This is of particular importance for analysis of samples from postmenopausal women, whose levels are extremely low. Recently, some groups have used liquid chromatography–tandem mass spectrometry (LC–MS/MS), which has much higher sensitivity and specificity.'
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505810/#R14Estrone can exert a role in BC only after being metabolised to estradiol inside breast cancer cells.
'Estrogens play a pivotal role in the development and proliferation of hormone-dependent breast cancer. Apart from free estrogens, which can directly activate the estrogen receptor (ER) of tumor cells, sulfo-conjugated steroids, which maintain high plasma concentrations even after menopause, first have to be imported into tumor cells by carrier-mediated uptake and then can be cleaved by the steroid sulfatase to finally activate ERs and cell proliferation'
https://www.frontiersin.org/articles/10.3389/fphar.2018.00941/fullFrom what I have understood, estrone levels are higher in postmenopausal women, independently of their obesity status. Obesity can further elevate estrone levels (but also estradiol levels), particularly in the peripheral tissues via fat cell metabolism. Thus, any impact of estrone in BC would mean the same for estradiol (endogenous or from HRT).
I'm not aware of any robust studies on BC and estrone, except for the ones that also consider estradiol as a factor.
BeaR.