Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Abstract

Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-β, and only norethisterone acetate, levonorgestrel and gestodene bind ERα. Comparative dose-response analysis revealed that progestins from the first three generations display similar androgenic activity to the natural androgen dihydrotestosterone for transactivation, while norethisterone acetate, levonorgestrel and gestodene are ERα agonists. We show for the first time that the anti-androgenic properties of progesterone and drospirenone are similar to the well-known AR antagonist hydroxyflutamide, while nomegestrol acetate is more potent and nestorone less potent than both hydroxyflutamide and progesterone. Moreover, we are the first to report that the older progestins, unlike progesterone and the fourth generation progestins, are efficacious ERα agonists for transrepression, while the selected progestins from the second and third generation are efficacious AR agonists for transrepression. Considering the progestin potencies and their reported free serum concentrations relative to dihydrotestosterone and estradiol, our results suggest that the progestins are likely to exert AR-, but not ERα- or ERβ-mediated effects in vivo.

Acquisition of Sexually Transmitted Infections among Women Using a Variety of Contraceptive Options: A prospective Study among High‐risk African Women

“…Conversely, the alternative explanation may be a protective effect of progestin based contraception against T. vaginalis likely due to hypo‐oestrogenic states which may not be conducive for persistence of T. vaginalis . However, though women using DMPA have suppressed levels of oestrogen , the same is not true for NET‐EN or implant users . Thus, this hypothesis does not fully explain the consistent finding across all the three progestin contraceptive groups.…”

Progesterone and Breast Cancer: an NCI Workshop Report

“…Another large Danish study involving 1.8 million women, followed on average for about 10.9 years, demonstrated that oral contraceptives containing synthetic progestins increased breast cancer risk (30); this is dependent on the type of progestin and duration of use. This study has major implications for the role of progestins in breast cancer and may, in fact, be in part due to the androgenic effects of synthetic progestins that are widely reported (31,32). However, a recent meta-analysis of worldwide epidemiological evidence supports the finding of increased breast cancer risk for women taking any form of progestin-containing HRT (33).…”

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner

“…Notably, these cells are devoid of the PR and AR (Su et al, 2012b). The GR, however, is present in C6 cells and MPA binds to the GR with a high affinity, acting as a partial to a full agonist for the GR (Koubovec et al, 2004(Koubovec et al, , 2005Su et al, 2012a,b;Louw-du Toit et al, 2014). We tested the hypothesis that MPA's effects on enzymatic activity and production of MMP-9 are mediated by the GR (Figure 4).…”