Although it is well known that some progesterone can effectively inhibit gonadotropin secretion and have a direct inhibitory effect on Leydig cell steroid production, it remains to be seen whether the combination of hormones has an additive agonist-antagonist-androgen effect. We therefore investigated the function of trestolone acetate in trans-activating androgen receptor (AR) dependent gene transcription, either alone or in combination with several progesterone hormones.

Trestolone acetate and progesterone transactivate gene transcription through progesterone receptors and AR

Since trestolone acetate is known to have a high affinity for progesterone receptors (PGR) and AR, we were interested in investigating the effects of trestolone acetate on transcriptional trans-activation through these two receptors. The effects of trestolone acetate on receptor-mediated reporter gene transcription were compared with those obtained with progesterone (P4), DHT, or testosterone, respectively. Pgr-mediated activity increases at concentrations (1×10−12 to 10−6 M) as shown in the figure. 1A. In these experiments, as an additional positive control, we also tested another synthetic progesterone, nestorone, a highly selective 19-norgestrol derivative with no androgenic and estrogenic activity (Kumar et al. 2000). 

As shown in the figure, trestolone acetate showed 2.38 times higher transcriptional activity than P4, with effective doses (ED50) of 7.46×10−10 and 1.78×10−9 M for trestolone acetate and P4, respectively. As shown in the figure. 1A, studies have shown that nestorone is 100 times more potent than P4 and ED50 is 6.25×10−12 M. Incubation in the presence of Mifepristone (RU486) resulted in inhibition of the trestolone acetate and nestorone effects of PGR-driven transcriptional activation (FIG. 1B). No different effects were observed with Mifepristone alone or with DHT (including the use of P4) on cells not transfected with PGR than with control vectors.