The incidence of menstrual irregularities, both primary and secondary amenorrhea, has been reported to be as high as 60%, with the highest incidence in younger athletes, suggesting possible adverse effects on bone development. It was hypothesized that in a rat model, suppressed hypothalamic activity via a gonadotropin-releasing hormone antagonist (GnRH-a) before onset of puberty would result in a relatively larger bone strength deficit compared with suppression after puberty. Hypothalamic suppression was achieved by providing GnRH injections. Animals received injections for 25 days either before puberty (pre group) (age 23–46 days) or after puberty (post group) (age 65–90 days). Body weights and uterine weights were measured. Serum estradiol was assayed. Mechanical strength of the right femora and histomorphometry of the left femur were measured. Suppression of the hypothalamic– pituitary–gonadal axis was confirmed by significant atrophy of uterine tissue and suppressed estradiol levels. The peak moment was significantly lower in the pre and post GnRH-a groups compared with control. The percentage difference of the average peak moment and stiffness values from the respective age-matched control groups yielded a greater percentage difference in the pre group. The cortical area was less in the GnRH-a-treated groups, but no significant difference between the relative deficits between pre and post groups were found. Hypothalimic–pituitary–gonadal axis suppression before puberty resulted in a significantly larger deficit in mechanical strength compared with postpubertal animals. The time before puberty may represent a time when skeletal strength is more compromised. Women experience both primary and secondary amenorrhea; however, the treatment may need to be different for each condition.
Purpose The purposes of this study were to suppress estradiol levels in adolescent (postpubertal rats) using gonadotropin-releasing hormone antagonist (GnRH-a) injections and to determine the changes in bone structure and mechanical strength. Methods In an Institutional Animal Care and Use Committee–approved study, female rats at 23 d of age were assigned to a baseline group (BL65; n = 10) sacrificed on day 65, a control group (Control; n = 15) sacrificed on day 90, or an experimental group (AMEN; n = 9) sacrificed on day 90 that received daily injections of GnRH-a for a 25-d period from 65 to 90 d of age (2.5 mg·kg−1 per dose). Results Body weights were similar on day 65; however, the AMEN group was significantly heavier than the Control group (17%, P = 0.001) on day 90. In the AMEN rats relative to the Control group, plasma estradiol levels were reduced by 36% (P = 0.0001) and plasma insulin-like growth factor 1 levels were 24% higher (P = 0.003). In the femur, there was no change in periosteal bone apposition or total cross-sectional area. The marrow area increased by 13.7% (P = 0.05) resulting in a 7.8% decrease in relative cortical area (P = 0.012), and endocortical bone formation rate increased by 39.4% (P = 0.04). Trabecular volume and number decreased by 51.5% (P = 0.0003) and 49.5% (P = 0.0003), respectively. The absolute peak moments of the tibiae and femurs were unchanged in the AMEN group relative to the Control group, but these were reduced by 8.8% (P = 0.03) and 7.5% (P = 0.09), respectively, when normalized by body weight. Conclusions Suppression of estradiol by 25 d of GnRH-a administration to 65-d-old (postpubertal) rats reduced trabecular volume and number by about 50%, increased endocortical bone turnover, and reduced relative cortical thickness without changing tibial and femoral total area. These changes in bone structure were associated with no change in absolute mechanical strength possibly because of increases in body weight or in insulin-like growth factor 1 concentrations.
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