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  • Our earlier experimental studies showed


    Our earlier experimental studies showed "neutral", i.e. non-proliferative, effects of progesterone but a large increase in proliferation using certain progestins; however, this was only in the presence of PGRMC1 [[13], [14], [15], [16], [17], [18], [19]]. The next step was to investigate whether this difference could be demonstrated in vivo, using a xenograft animal model [22]. With norethisterone, tumor growth was faster for PGRMC1-transfected xenograft tumors, but not with progesterone. However, it should not be concluded from these xenograft tumor model results that progesterone may be safe in breast cancer survivors. Nevertheless, this in-vivo model can complement in-vitro studies investigating proliferation of pre-existing breast cancer cells, which is the main mechanism for breast cancer development during MHT. Our earlier animal study [22], encouraged us to perform the present study to investigate the effect of dydrogesterone. Its pharmacological profile is very similar to that of progesterone, and therefore similar effects to progesterone could be expected [23]. To minimize animal experiments, our first step was to perform an in-vitro study to select, from seven synthetic progestogens, the comparator which elicited the strongest proliferative effect. We then compared this progestogen with dydrogesterone and progesterone in an animal xenograft model. The aim of this main study was to investigate whether with dydrogesterone similar "neutral" effects, i.e. no breast cancer tumor-growth, could be demonstrated as observed with progesterone by testing for the first time these progestogens head to head using the already validated xenograft model [22] and further investigating the importance of PGRMC1 for progestogen-dependent proliferative effects.
    Discussion Regarding dydrogesterone, we found significant proliferation compared with progesterone in the PGRMC1-transfected T47D 2b3a inhibitors (Fig. 2); however, we are very cautious about drawing conclusions from this slight difference with regard to a different risk profile between progesterone and dydrogesterone, as suggested in the E3N cohort study [11]. Progesterone’s "neutral" effect in non-transfected cells as well as in PGRMC1 cells has been observed also in all our earlier studies using MCF7 cells, in contrast to the strong proliferative effect of other tested synthetic progestogens, especially norethisterone [[13], [14], [15], [16], [17], [18], [19],24]. In contrast to our earlier studies, we used T47D cells representing luminal A subtype (ERα+, PR+/−, and HER2-). T47D cells were originally derived from a metastatic pleural effusion of a ductal breast carcinoma and are now thought to be ideal for elucidating progestogen effects; they are also recommended for xenograft tumor models due to their tumorigenic properties in the presence of estrogen [[25], [26], [27]]. Indeed, in our study tumor growth was much faster in T47D than in MCF7 xenografts (Fig. 7, Fig. 8). The question may arise as to whether our progestogen concentrations reflect the clinical situation with MHT. For most progestogens, for example for progesterone (200 mg/day) and norethisterone (1–5 mg/day), this is in the range of about 10 nM [24]. This was used as the lowest concentration. We also tested higher concentrations, as they could be present intracellularly and in tissue. In the tests to investigate whether the significant effects shown with norethisterone and dydrogesterone were still present when those progestogens were combined with estradiol, we used estradiol concentrations in the range achieved with MHT, i.e. about 10−10M [24]. We also used the lower concentration of 10-12M to more clearly detect progestogen-induced effects. Compared with E2 alone, only with NET, not with dydrogesterone, in the PGRMC1-transfected cells were significant additional effects seen, especially at the lower concentration of E2 (10–12M); moreover, this was over twice as strong when in continuous combination (Fig. 6, 117%) than when in sequential combination (Fig. 4, 51%).