Effects of 17β-estradiol and trimegestone alone ,and in combination ,on the bone and uterus of ovariectomized rats

Abstract

Trimegestone is a novel norpregnane progestin ,which is being developed ,in combination with 17β-estradiol ,for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis.A model of osteoporosis in the ovariectomized rat has been used to evaluate the effects of 17β-estradiol and trimegestone ,alone and in combination ,on bone and uterus in these animals.Twotreatment protocols were investigated ,preventive with treatment starting immediately after ovariectomy and curative with treatment starting 1 or 6 months after ovariectomy. 17β-Estradiol wasadministered subcutaneously at a dose of 10 μg/kg/day with trimegestone or norethisterone being administered orally at a dose of 1 mg/kg/day; treatment was given 5 days per week. Treatment onboth protocols was for 6 months.Given alone ,17β-estradiol maintained bone mass ,either partially or completely ,when given on the preventive protocol ,or on the curative protocol withtreatment starting 1 month after ovariectomy; it did not restore bone mass when given on the curative protocol with 6 months lapsing between ovariectomy and start of treatment. Trimegestone did not blockthe beneficial effects of 17β-estradiol on bone. 17β-Estradiol induced uterine hypertrophy on all these protocols and this was blocked completely by trimegestone.Trimegestoneadministered alone had no effect on bone or uterus but ,when given in combination with 17β-estradiol ,it did not inhibit the effect of 17β-estradiol in maintaining bone mass butcompletely blocked its uterotropic effect. Norethisterone at a similar dose did not inhibit the effects of 17β-estradiol on bone but also did not block its uterotropic effect.