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

Trimegestone is a novel norpregnane progestin, which is being developed, in combination with 17 beta -estradiol, for the treatment of menopausal sympt oms and prevention of postmenopausal osteoporosis. A model of osteoporosis in the ovariectomized rat has been used to evaluate the effects of 17 beta -estradiol and trimegestone, alone and in combination, on bone and uterus i n these animals. Two treatment protocols were investigated, preventive with treatment starti ng immediately after ovariectomy and curative with treatment starting 1 or 6 months after ovariectomy. 17 beta -Estradiol was administered subcutaneou sly at a dose of 10 mug/kg/day with trimegestone or norethisterone being ad ministered orally at a dose of 1 mg/kg/day; treatment was given 5 days per week. Treatment on both protocols was for 6 months. Given alone, 17 beta -estradiol maintained bone mass, either partially or c ompletely, when given on the preventive protocol, or on the curative protoc ol with treatment starting 1 month after ovariectomy; it did not restore bo ne mass when given on the curative protocol with 6 months lapsing between o variectomy and start of treatment. Trimegestone did not block the beneficia l effects of 17 beta -estradiol on bone. 17 beta -Estradiol induced uterine hypertrophy on all these protocols and this was blocked completely by trim egestone. Trimegestone administered alone had no effect on bone or uterus bist, when given in combination with 17 beta -estradiol, it did not inhibit the effect of 17 beta -estradiol in maintaining bone mass but completely blocked its uterotropic effect. Norethisterone at a similar dose did not inhibit the ef fects of 17 beta -estradiol on bone but also did not block its uterotropic effect.