Not all of the biological
Not all of the biological activities exhibited by progestogens (Table 1) are mediated via binding to SRs. For example, the anti-estrogenic action of progestogens in the 3-AP is due to the progestogen-bound PR suppressing ER gene expression, and consequently the ability of the cell to respond to estrogen. In addition, progestogen-bound PR activates the 17β-hydroxysteroid dehydrogenase type 2 enzyme which converts active estradiol to inactive estrone, as well as activating the estrone-sulfotransferase which causes the conjugation of estrone . All the synthetic progestins in Table 1 display anti-estrogenic activity via this mechanism in animal models . Similarly, Prog displays anti-androgenic effects, not via binding to the AR, but by inhibition of 5α-reductase activity, and hence decreasing the conversion of testosterone to the more active androgen, DHT. It is thus plausible that synthetic progestogens elicit similar effects. Indeed, the synthetic progestogen, dienogest, that has low relative binding affinity for the AR and potent anti-androgenic activity , has been shown to inhibit 5α-reductase activity . The relative contribution of these non-receptor off-target effects will vary depending on the relative concentrations of the off-target proteins in different model systems.
Conclusions Reported binding data in the literature are highly variable, most likely due to multiple factors, including methodological differences, and differential affinities of progestogens for binding to the MR, AR and GR, which exhibit varying relative concentrations in different assay systems. The different binding affinities of progestogens for different SRs are likely to be a major determinant of differential actions of progestogens in a tissue- and cell-specific manner and be highly relevant to side-effects of progestogens. For example, since MPA has a relatively high affinity for the ubiquitously expressed GR  and is widely used in hormonal therapy and contraception, this raises important questions about glucocorticoid-like side-effects of MPA on cardiovascular effects, breast cancer, immune function, bone density and susceptibility to infectious diseases , , , , , , , , , . It is thus essential that accurate affinities of progestogens are determined for different SRs, in order to better assess their potential differential side-effect profiles and aid in new drug design. When designing binding experiments, potential confounding factors such as metabolism, off-target binding to other receptors, methodology and analysis thereof, need to be carefully considered, since they can lead to shifts in the IC50 values, Hill slopes and hence inaccurate RBAs and K values.
Introduction Breast cancer is one of the most common invasive cancers in women worldwide, comprising 22.9% of invasive cancers in women  and 16% of all female cancers . Important studies such as the Women\'s Health Initiative (WHI) and the Million Women Study (MWS) showed the probable relationship between progestogen treatment and increased risk of breast cancer in postmenopausal women , . In contrast to this, in the French E3N-EPIC trial which enrolled about 80,000 postmenopausal women, hormone therapy including progesterone or dydrogesterone did not induce an increased breast cancer risk. Instead, hormone therapy containing the progestins medroxyprogesterone acetate (MPA) or norethisterone (NET) was associated with a significantly increased risk . Convincing evidence for the increased breast cancer risk related to progestogens is associated with the results of the WHI estrogen mono-arm trial which showed a reduction in breast cancer risk, especially in patients with more than 80% adherence to study medication . The mechanism(s) by which progestogens may increase breast cancer risk remains still unknown. In the present review, we will briefly summarize the available data on genomic and non-genomic effects of progestins in the breast. For progesterone (P) these actions are already published in numerous reviews ,  and they will be mentioned only briefly.