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  • br Clinical studies br Practical implications for

    2019-07-10


    Clinical studies
    Practical implications for young women
    Conclusion Research on the oncogenic mechanism of hormones has advanced dramatically in the latter years. The finding that progestogens are more powerful determinants of risk than estrogens in breast cancer has been added to advances in the molecular background. The discovery of the implication of RANKL, and its receptor RANK, has opened new research areas. As a natural extension, recent work is investigating the value of RANKL/RANK as biomarkers useful in better discerning the prognosis of breast cancer. Both survival and metastatic potential have been related with RANK dna synthesis [31], and this feature has been also confirmed in the disease affecting young women [32]. Furthermore, modulation of the RANK pathway is being actively investigated as a potential target to limit tumor aggressiveness [33]. The discovery of new molecules with potential to modulate the receptor has added consistency to the observations on the oncogenic role of estrogens and progestogens in the breast. Breast cancer keeps being a crucial issue that conditions the reluctance of many young women to use hormones for contraceptive purposes. The current information, however, is much limited to OC, the popular pill, and incipient information is being obtained on the impact of progestogen-only preparations, including both the levonorgestrel-loaded IUD and progestogen-only pills. Of much interest to reassure young, usually less than 45 years, users of hormonal contraception, clinical studies persistently report that the specific increased risk with hormonal contraceptives is very low. In absolute terms the risk limits to 1 extra breast cancer for 7690 users during 1 year [6]. Of course, such a low increased risk prevents any analysis on mortality, which most probably will be nil. The new clinical data confirming protection against ovarian and endometrial cancer in the long term should also be added in order to better support the decision of women considering the intake of hormonal contraceptives [6].
    There is still controversy about menopausal hormone therapy (MHT) and the risk of breast cancer in postmenopausal women [1,2]. The Women\'s Health Initiative (WHI) found [3,4] that the risk is mainly dependent on the progestogen component, and this conclusion has been supported in various observational studies [1,2,5]. It has been suggested that the increased risk is related to the use of synthetic progestogens, and that norethisterone, mainly used in Europe, especially Scandinavia, may confer the highest risk [6]. However, there are no prospective randomized controlled trials, and conclusions have been based only on a few observational studies [[7], [8], [9]]. Progesterone and its retro-isomer have been associated with a better risk profile regarding breast cancer than synthetic progestogens for at least 5–8 years. However, the issue is complex, as can be seen in successive publications from the French E3N cohort study, which initially reported no increased risk with progesterone or dydrogesterone [10], but with a duration of treatment of over five years the risk was increased (1.31; 95% CI 1.15–1.48), although it was still lower than with synthetic progestogens (2.02; 95% CI 1.86–2.26) [7]. Analyzing breast cancer subtypes [11], ‘ever use’ of estrogen plus progesterone was not associated with an elevated risk of any breast cancer subtype, whereas dydrogesterone was associated with an increase in lobular carcinoma [RR 1.7 (95% CI 1.1–2.6)]. Therefore, there may be slight differences in the risk profiles of progesterone and dydrogesterone. Further studies comparing dydrogesterone versus progesterone are urgently needed. There are a variety of different effects leading to possible breast cancer development which are dependent on the action of progestogens [1,2,5]. Our research in recent years has focused on progesterone receptor membrane component 1 (PGRMC1), which is found to be overexpressed in breast cancer tissue and to predict a worse diagnosis [12]. We found that the proliferative effects of certain synthetic progestogens are strongly increased in the presence of PGRMC1 [[13], [14], [15], [16], [17], [18], [19], [20]]. An editorial by F. Stanczyk [21], commenting on our research, pointed out that the results in the WHI could be explained by overexpression of PGRMC1.