OCs were developed in the early 1960s, comprising EE, a synthetic estrogenic compound. Despite lowered hormone doses, in certain cases, OCs may induce serious arterial or venous thromboembolic complications suggesting a disturbed regulation of blood clotting. Since estrogen regulated genes have crucial roles in the balanced hepatic synthesis of factors of coagulation and fibrinolysis, thromboembolic events associated with OC use suggest a deregulation of ERs via partial inhibition and compensatory stimulation yielding estrogen-like properties.
Use of OCs comprising synthetic estrogen exhibits ambiguous correlations with cancer risk depending on the regulatory features of affected organs. In OC user women, overall breast cancer risk is slightly increased, while the risks for ER-negative and triple negative breast cancers are significantly elevated. The increased prevalence of poorly differentiated breast cancers among OC users reveals imbalanced ER activations via liganded and unliganded pathways. In contrast, endometrial and ovarian cancer risks are reduced in OC users, as synthetic estrogen upregulates liganded ER activation via an inhibition of non liganded pathways. Consequently, OCs may improve the regulation of these female organs as they are primarily dependent on the hormonal activation of ERs.
These highly controversial correlations between OC use and cancer prevalence at different sites reveals that EE even in low doses is not a pure agonist of ERs, but it is an endocrine disruptor inducing alterations in estrogen regulated gene expression. Despite all experienced complications of OC use, EE is a widely used estrogenic compound in medical practice even today. All adverse effects associated with OC use are mistakenly attributed to characteristic concomitants of increased endogenous estrogen levels.
For MHT analysis, both synthetic estrogens and CEEs extracted from biological samples were prescribed. In the early MHT studies, hormone use was designated simply as exogenous estrogen treatment without discrimination between natural and synthetic estrogen formulas. Among postmenopausal women, the use of estrogens with different origin and even their combinations with synthetic progestogens resulted in a chaos of quite controversial clinical experiences concerning the risks for arterial and venous thromboembolism and for cancer of the breasts. Wide spread use of MHT has provided an expanding clinical database suggesting crucial roles of estrogen hormone in the development of coronary heart disease and breast cancer. This belief has directed both breast cancer care and the a significant portion of the community on a false track. Health professionals could not recognize that behind the experienced adverse effects of MHT use, various defects in estrogen signaling may be delineated instead of an excessive estrogen activation of ERs.
From 1971, antiestrogenic compounds were introduced for breast cancer therapy. Despite initial enthusiasm, the antiestrogen blockade of ERs; the highest regulators of genomic machinery, resulted in many failures in breast cancer care either as a prophylactic or therapeutic measure. In antiestrogen responsive breast cancer cells, the chemical shock may upregulate the remnants of their regulatory capacity inducing a compensatory increased expression and liganded activation of ERs as well as a transient tumor regression. In contrast, tumor cells unresponsive to antiestrogen treatment may show completely blocked liganded ER-activation, while an upregulation of growth factor receptor signals and acquired activating mutations strive to strengthen the unliganded activation of ERs. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of ERs is an aggressive survival technique, whilst it is a compensatory effort against the artificial liganded ER-blockade. Unfortunately, even an extreme unliganded ER-activation is incapable of DNA-repair when the liganded activation is completely blocked and the result will be an unrestrained proliferation of tumors. The capacity of estrogen activated ERs for genome modification in emergency states provides excellent possibilities for estrogen/ER use against all human diseases including cancer.
In 2002, the publication of Women's Health Initiative (WHI) investigators reported greater harm than benefit of combined MHT (Premarin plus medroxyprogesterone-acetate (MPA)) resulting in a precipitous decrease in estrogen and progestin use and a serious re-evaluation of menopausal hormone therapy. Mistakenly, Premarin was blamed for the experienced adverse effects instead of MPA; however, the results of HRT studies in the UK revealed that progestin formulas may be much more dangerous for the health of female breasts than estrogens. Nevertheless, the next step was an increased interest in introducing alternative approaches to manage menopausal symptoms preferring the use of "bioidentical" synthetic hormones instead of Premarin.
In 2004, striking results of a randomized placebo controlled prospective MHT study were reported by WHI investigators. Postmenopausal women with prior hysterectomy were treated with 1 dose and 1 schedule of oral CEE (Premarin 0.625 mg/day). After a median follow up of 5.9 years, the incidence of breast cancer was lower in the estrogen group, as compared with the placebo group (HR: 0.77). The authors could hardly believe the beneficial effect of unopposed Premarin treatment and suggested further investigations.
Retrospective analyses of the results of specific MHT studies using CEE alone, clearly justified that natural estrogen use without synthetic progestin is highly beneficial against thromboembolism, cardiovascular disease, dyslipidemia, bone loss and breast cancer.
In 2011, WHI investigators published the results of an extended, 10.7 year follow-up study continuing after a previous 5.9 years of Premarin use. In the previous study, among postmenopausal women without a uterus, a lower incidence of breast cancer was experienced in the Premarin group as compared with the placebo group and this result became statistically significant with the extended period of follow-up. WHI investigators explained their result with the uterine extirpated status of women.
In 2019, in San Antonio Breast Cancer Symposium, WHI investigators presented an update on breast cancer findings from two WHI randomized controlled trials with more than 19 years of follow up. CEE alone resulted in a significant 23% reduction in breast cancer incidence, while CEE plus MPA yielded a significant 29% increased risk of breast cancer. In addition, death from breast cancer was significantly reduced (44%) with CEE treatment alone, while showed a borderline significant increase (45%) with CEE plus MPA treatment.
The long term benefit of Premarin for women's health may be unique and may not be applied to other (synthetic) estrogen preparations. After 19 years, the advantageous anticancer effect of natural estrogens may be explained by their capacity for DNA repair via activating mutations.