The pharmacological profile of a novel norpregnane progestin (trimegestone)

Abstract

Trimegestone is a novel norpregnane progestin that is being developed, in combination with estradiol, for the treatment of menopausal symptoms. The pharmacological characteristics of trimegestone have been evaluated in both in vitro and in vivo test systems, and compared with reference progestins. Interaction with hormonal steroid receptors from animal tissues and with human recombinant receptors in vitro has demonstrated that trimegestone has a high specificity and potency for the progesterone receptor, no affinity for the estrogen receptor, and weak affinity for androgen, glucocorticoid and mineralocorticoid receptors. With respect to progestomimetic activity in vivo, trimegestone was more potent than reference progestins in the endometrial transformation test in the rabbit, preventing the uterotrophic effect of estradiol in the immature mouse bioassay, and had more effect on traumatic deciduoma formation and greater oral antiovulatory activity in the rat. In vivo, trimegestone effectively maintained pregnancy in the rat, but was devoid of any uterotrophic activity. Trimegestone showed no androgenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity, but did show some antiandrogenic and antimineralocorticoid activity at higher doses. Administration of trimegestone to ovariectomized rats, in combination with estradiol, inhibited the uterotrophic effects of estradiol. At doses up to 1 mg/kg intravenously and 30 mg/kg orally, trimegestone was not associated with any unwanted pharmacological effects. Overall, the results show trimegestone to have a favorable pharmacological profile with potent progestomimetic activity.

Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio)

“…In our study there was no tendency towards female bias at concentrations up to 1122 ng L −1 , using 34-37 fish in the P4-treated groups and 40 fish in the control group. Furthermore, P4 has very low affinity for the human ER and does not activate the zebrafish ERs (Menuet et al, 2002;Philibert et al, 1999), making female bias via activation of ERs unlikely.…”

“…To elucidate possible involvement of AR and PR activation, we used one androgenic and one non-androgenic progestin as test compounds. Levonorgestrel (LNG) was chosen as the model androgenic progestin due to its high AR affinity (58% of that of testosterone to rat AR) (Africander et al, 2011;Philibert et al, 1999;Runnalls et al, 2013), environmental presence (Al-Odaini et al, 2010;Chang et al, 2011;Vulliet and Cren-Olivé, 2011;Vulliet et al, 2008), and known androgenic effects in fish (Runnalls et al, 2013;Svensson et al, 2013Svensson et al, , 2014. P4 was chosen as the model non-androgenic progestin due to its low AR affinity (3% of that of testosterone to rat AR) (Bain et al, 2015;Bauer et al, 2000;Philibert et al, 1999), frequent environmental detection (Ammann et al, 2014;Chang et al, 2011;Velicu and Suri, 2009;Vulliet and Cren-Olivé, 2011;Vulliet et al, 2008), and absence of androgenic effects on fish (Jolly et al, 2006;Jones et al, 2001).…”

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

“…Norpregnane derivatives, including nomegestrol acetate and promegestone, appear to have a very high progestational activity, and unlike nortestosterone derivatives, they do not possess androgenic, estrogenic, or glucocorticoid activity. 20 Norpregnane derivatives bind almost exclusively to the progesterone receptor and do not interfere with the other steroid receptors. Their affinity for the progesterone receptor is higher than the progesterone one.…”

The other side of progestins: effects in the brain

“…Among these, there are the third-generation progestins (desogestrel or gestodene), derived from LNG group, developed to decrease androgenic activity (LeBlanc & Laws 1999), and the fourth-generation progestins. In this latter group, nomegestrol acetate exhibits partial anti-androgenic activity (Lello 2010, Van Diepen et al 2011) DNG, DRSP, and trimegestone have a significant anti-androgenic activity, whereas nestorone has no activity via the AR (Fotherby 1990, Philibert et al 1999, Schindler et al 2003.…”