gestodene and trimegestone

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.

Topics: Administration, Oral; Administration, Topical; Animals; Binding, Competitive; Endometrium; Female; Humans; Injections, Subcutaneous; Levonorgestrel; Medroxyprogesterone; Mice; Norethindrone; Norpregnenes; Progesterone Congeners; Promegestone; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Receptors, Progesterone; Specific Pathogen-Free Organisms; Uterus