Roth C, Leonhardt S, Seidel C, Luft H, Wuttke W, Jarry H
Children's Hospital, University of Göttingen, Göttingen, Germany.
Pediatr Res. 2000 Oct;48(4):468-74. doi: 10.1203/00006450-200010000-00009.
GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by desensitization of pituitary GnRH receptors. Little has been published about the use of GnRH antagonists such as cetrorelix to control the onset of puberty and whether they are potentially advantageous compared with GnRH agonists. We conducted two multigroup experiments (12 and 10 d, respectively) treating prepubertal/peripubertal female rats with either the GnRH agonist triptorelin or buserelin and compared them with rats treated with the GnRH antagonist cetrorelix and controls to assess the effects on pubertal progress and serum hormones. In the second experiment, the effects of buserelin and cetrorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and the alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by delayed vaginal opening, lower ovarian weights, and lower serum estradiol levels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin experiment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subunit were stimulated by buserelin but not by cetrorelix. Even though all three of these GnRH analogues inhibited gonadal development and delayed the onset of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effects. We conclude from this female rat model that cetrorelix may offer advantages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.
促性腺激素释放激素（GnRH）激动剂是治疗因促性腺激素分泌过早刺激引起的性早熟的既定疗法。据报道，在初始刺激（“激发”）后，它们通过使垂体GnRH受体脱敏来降低促黄体生成素（LH）的分泌。关于使用GnRH拮抗剂（如西曲瑞克）来控制青春期启动以及与GnRH激动剂相比是否具有潜在优势的报道很少。我们进行了两项多组实验（分别为12天和10天），用GnRH激动剂曲普瑞林或布舍瑞林治疗青春期前/青春期早期雌性大鼠，并将它们与用GnRH拮抗剂西曲瑞克治疗的大鼠及对照组进行比较，以评估对青春期进程和血清激素的影响。在第二项实验中，还研究了布舍瑞林和西曲瑞克对垂体中GnRH受体、LH-β、卵泡刺激素-β（FSH-β）和α亚基基因表达的影响。通过阴道开口延迟、卵巢重量降低和血清雌二醇水平降低确定，西曲瑞克、曲普瑞林和布舍瑞林均延缓了青春期启动。然而，虽然两种激动剂均刺激LH和FSH水平，但它们被西曲瑞克抑制。在西曲瑞克与布舍瑞林的实验中，与对照组相比，西曲瑞克治疗的大鼠垂体中GnRH受体和LH-β亚基的基因表达显著降低，而布舍瑞林几乎没有影响。布舍瑞林刺激FSH-β和α亚基的表达，但西曲瑞克无此作用。尽管所有这三种GnRH类似物均抑制性腺发育并延迟青春期启动，但GnRH激动剂对垂体-性腺轴具有刺激和抑制作用，而西曲瑞克仅发挥抑制作用。我们从这个雌性大鼠模型得出结论，与GnRH激动剂治疗相比，西曲瑞克在更可控地医学治疗性早熟方面可能具有优势。
