Comparison of the effects of add-back therapy with various natural oestrogens on bone metabolism in rats administered a long-acting gonadotrophin-releasing hormone agonist

The hypoestrogenic state induced by gonadotrophin-releasing hormone agonist (GnRHa) has been shown to be effective in the treatment of oestrogen-depen dent disorders but to induce bone loss. Adding back low doses of oestrogen in GnRHa therapy has been proposed to prevent bone loss. The purpose of thi s study is to assess the efficacy of add-back therapy with different natura l oestrogens such as oestrone (OE1), oestradiol (OE2) and oestriol (OE3). T hree-month-old female rats (250 g) were subcutaneously administered microca psules of leuprorelin acetate in doses of 1 mg/kg of body weight every 4 we eks. GnRHa therapy lasted 16 weeks, and pellets of OE1, OE2 or OE3 (0.5 mg/ pellet, 60 day release), as an add-back agent, were implanted at 8 weeks of treatment. At the end of treatment, GnRHa alone decreased bone mineral den sity of the femur and lumbar vertebrae, and increased serum levels of bone metabolic markers such as alkaline phosphatase and osteocalcin levels. As f or cancellous bone histomorphometry, GnRHa decreased bone volume while it i ncreased osteoid volume, osteoid surface, eroded surface, mineral appositio n rate and bone formation rate. All the oestrogens tested prevented these c hanges caused by GnRHa therapy. GnRHa induced a significant increase in bod y weight and a marked reduction in uterine weight, which was not observed i n OE1 or OE2 add-back group. Body weight and uterine weight of the OE3 add- back group were the same as those of the GnRHa group. These findings indica te that GnRHa induces high turnover bone loss which can be prevented by con comitant administration of natural oestrogens such as OE1, OE2 and OE3 to t he same extent. In addition, OE3 is unique in that it is much less effectiv e than OE1 and OE2 in blocking body weight gain and in promoting growth of uterine tissues. Because of its tissue-selective actions, OE3 could be cons idered as one of the most appropriate oestrogens used for GnRHa add-back th erapy.