Broekmans F J, Bernardus R E, Broeders A, Berkhout G, Schoemaker J
Department of Obstetrics and Gynecology, Vrije Universiteit, The Netherlands.
Clin Endocrinol (Oxf). 1993 Jun;38(6):579-87. doi: 10.1111/j.1365-2265.1993.tb02138.x.
This study was focused on the pattern of LH release from the pituitary during the initial response to high dose GnRH agonist administration. Secondly, the pattern of LH release and the pituitary responsiveness to physiological and pharmacological stimulation during long-term pituitary suppression by a high dose GnRH agonist was studied. In addition, the relation between serum agonist levels and pituitary function and responsiveness was investigated.
DTrp6GnRH in microcapsules (Decapeptyl CR) was administered i.m. to 12 women on the third day of the cycle. High-rate blood sampling was carried out during the first 48 hours after the injection. Secondly, high-rate blood sampling for 6 hours and a GnRH challenge were performed before and weekly after administration, from week 4 till week 9. All samples were assayed for LH and FSH. LH patterns were analysed by applying a computerized pulse detection program. In the second or third week an oestradiol benzoate test was performed. Finally, triptorelin levels were measured before and weekly after administration.
Twelve patients, suffering from tubal infertility and recruited from the waiting list for in-vitro fertilization/embryo transfer (IVF/ET) participated in the study.
During the first 48-hour period, LH and FSH levels demonstrated a rapid rise to peak values after 4 hours, subsequently declining to nearly normal levels. E2 rose to peak values at 12 hours and returned to the follicular range thereafter. LH pulse patterns showed a rapid increase in pulse intervals leading to a near absence of LH pulses at the end of the 48-hour period. From the fourth till the seventh week after agonist administration, LH pulse patterns showed a markedly increased pulse interval, decreased pulse amplitude, and a severely decreased mean LH level. In the same period, LH responses to GnRH were severely blunted or absent. Restoration of the pre-injection LH pulse pattern and the LH response to GnRH was observed during the eighth and ninth week. Oestradiol benzoate challenges showed an E2 rise to preovulatory levels in response to the injections. However, no changes were observed in LH and FSH concentrations. Triptorelin levels showed a peak within 48 hours and gradual decline towards pretreatment values in week eight.
It is concluded from the study, that after administration of triptorelin depot in the early follicular phase, desensitization of the pituitary starts to develop within 24 hours. Pituitary responsiveness is completely absent in the second week and continues to exist until the eighth week after injection, when the agonist has disappeared from the circulation. These findings suggest profound alterations in GnRH receptor availability and post-receptor pathways, that prevent the pituitary from responding to physiological stimuli.
本研究聚焦于高剂量促性腺激素释放激素（GnRH）激动剂给药初期垂体促黄体生成素（LH）的释放模式。其次，研究了高剂量GnRH激动剂长期抑制垂体期间LH的释放模式以及垂体对生理和药理刺激的反应性。此外，还研究了血清激动剂水平与垂体功能及反应性之间的关系。
在月经周期的第3天，对12名女性肌肉注射微囊化的DTrp6GnRH（曲普瑞林长效注射剂）。注射后的前48小时进行高频采血。其次，在给药前以及给药后第4周至第9周每周进行一次6小时的高频采血及GnRH激发试验。所有样本均检测LH和促卵泡生成素（FSH）。通过应用计算机脉冲检测程序分析LH模式。在第二或第三周进行苯甲酸雌二醇试验。最后，在给药前及给药后每周检测曲普瑞林水平。
12名因输卵管性不孕而从体外受精/胚胎移植（IVF/ET）等候名单中招募的患者参与了本研究。
在最初的48小时内，LH和FSH水平在4小时后迅速升至峰值，随后降至接近正常水平。雌二醇（E2）在12小时升至峰值，此后恢复至卵泡期范围。LH脉冲模式显示脉冲间隔迅速增加，导致在48小时结束时几乎无LH脉冲。在激动剂给药后的第四至第七周，LH脉冲模式显示脉冲间隔明显增加、脉冲幅度降低以及平均LH水平严重下降。在同一时期，LH对GnRH的反应严重减弱或消失。在第八和第九周观察到注射前LH脉冲模式及LH对GnRH反应的恢复。苯甲酸雌二醇激发试验显示注射后E2升至排卵前水平。然而，LH和FSH浓度未观察到变化。曲普瑞林水平在48小时内达到峰值，并在第八周逐渐降至治疗前水平。
从本研究得出的结论是，在卵泡早期给予曲普瑞林长效注射剂后，垂体脱敏在24小时内开始发展。垂体反应性在第二周完全缺失，并持续至注射后第八周，此时激动剂已从循环中消失。这些发现提示GnRH受体可用性及受体后途径发生了深刻改变，从而阻止垂体对生理刺激产生反应。
