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

Abstract

The hypoestrogenic state induced by gonadotrophinreleasing hormone agonist (GnRHa) has been shown to be effective in the treatment of oestrogen-dependent 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 this study is to assess the efficacy of add-back therapy with different natural oestrogens such as oestrone (OE 1 ), oestradiol (OE 2 ) and oestriol (OE 3 ). Three-month-old female rats (250 g) were subcutaneously administered microcapsules of leuprorelin acetate in doses of 1 mg/kg of body weight every 4 weeks. GnRHa therapy lasted 16 weeks, and pellets of OE 1 , OE 2 or OE 3 (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 density of the femur and lumbar vertebrae, and increased serum levels of bone metabolic markers such as alkaline phosphatase and osteocalcin levels. As for cancellous bone histomorphometry, GnRHa decreased bone volume while it increased osteoid volume, osteoid surface, eroded surface, mineral apposition rate and bone formation rate. All the oestrogens tested prevented these changes caused by GnRHa therapy. GnRHa induced a significant increase in body weight and a marked reduction in uterine weight, which was not observed in OE 1 or OE 2 add-back group. Body weight and uterine weight of the OE 3 add-back group were the same as those of the GnRHa group. These findings indicate that GnRHa induces high turnover bone loss which can be prevented by concomitant administration of natural oestrogens such as OE 1 , OE 2 and OE 3 to the same extent. In addition, OE 3 is unique in that it is much less effective than OE 1 and OE 2 in blocking body weight gain and in promoting growth of uterine tissues. Because of its tissue-selective actions, OE 3 could be considered as one of the most appropriate oestrogens used for GnRHa add-back therapy.

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

“…Because these deviations resolve within 2-3 weeks following colonization with normal flora (3), GF mice that were colonized with the microbiota of conventional mice were included in the study to control for phenotypic aberrations of GF mice not reversed by microbial colonization. In addition, because surgical procedures such as ovx are not technically feasible within a GF isolator, we utilized the GnRH agonist leuprolide to alter the production of ovarian sex steroids; leuprolide has been used previously to induce bone loss in rodents (19,20).…”

“…In addition, many genetic and nongenetic factors intensify the negative impact of estrogen deficiency on the skeleton (17,18). In mice, the effects of estrogen depletion are modeled by ovx or by treatment with gonadotropin-releasing hormone (GnRH) agonists (19,20). At the cellular level, the central mechanism by which sex steroid deficiency induces bone loss is via an increase in osteoclast formation (21,22) and osteoclast lifespan (23,24).…”

Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

“…Because our experiments were very short in duration, this may be an important difference. In fact, in long-term experiments, leuprolide has been shown to cause significant bone loss in rats over 16 wk of treatment, and a 1-yr comparison of leuprolide with OVX demonstrated equivalent degrees of bone loss in rats (31)(32)(33). It is worth noting, however, that mice undergo a postpartum estrous cycle before gonadotrophin secretion is inhibited by suckling (34).…”

Medical Treatment of Uterine Leiomyoma

“…2 A few publications have addressed this issue. 67,70,71 One report compared 3 types of estrogen and recommended the use of the natural estrogen ''estriol'' due to its tissue-selective actions, which prevent body weight gain and limit the growth of uterine tissues. 71 Combined Estrogen and Progestagen…”