Department of Obstetrics and Gynecology, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Reprod Biol Endocrinol. 2013 Mar 1;11:16. doi: 10.1186/1477-7827-11-16.
With the continuous improvement of surgery and chemotherapeutic treatments, many tumour patients increasingly achieve long-term survival and can even be completely cured. However, platinum-containing drugs, which are widely used to treat a variety of types of cancer, cause menstrual disorders and ovarian failure, which in turn lead to infertility. Thus far, gonadotropin releasing hormone (GnRH) agonist (GnRHa) and antagonist (GnRHant) are reported to act as protective agents of the ovary in chemotherapy through the inhibition of the female gonadal axis. Nevertheless, they both have disadvantages that limit their use. GnRHa causes a flare-up effect during the first week after administration, and no long-acting GnRHant agent is available. GnRHa combined with GnRHant may prevent the flare-up effect of GnRHa and rapidly inhibit the female gonadal axis. Several clinical studies with small sample sizes have reported controversial conclusions. In this strictly controlled animal study, we investigated the advantages of combination treatment with GnRHa and GnRHant.
Rats aged 12 weeks were divided into six groups: Control, cisplatin (CDDP), GnRHa, GnRHant, Combination (sht, short-term) and Combination (lng, long-term) of GnRHa and GnRHant. The last four groups received Triptorelin (1 mg/kg·d, for 14 days), Cetrorelix (0.5 mg/kg·d, for 10 days), a combination of Triptorelin (1 mg/kg·d, for 10 days) and Cetrorelix (0.5 mg/kg·d, for 10 days) in the long-term group and for 3 days in the short-term group. The Control and CDDP groups received saline (1 ml/kg·d, for 10 day). Then, all groups apart from the Control group received cisplatin (1 mg/kg·d, for 10 days), and the Control group received another 10 days of saline as described above. Blood samples were collected to detect the serum levels of E2, LH and FSH. Observation of oestrous cyclicity was also performed after drug administration. Finally, bilateral ovaries were collected for histological study and follicle counting.
We observed a flare-up effect in rats treated with GnRHa, but not in any of the combination groups. The percentage of normal cyclicity increased from 0% in the CDDP group to 25.0%, 33.3%, 66.7% and 41.7%, in the GnRHa, GnRHant, combination (lng) and combination (sht) groups, respectively. Pretreatment with GnRHa, GnRHant and combination (lng) significantly protected the primordial follicles from destruction by preserving 57.6%, 63.4%, 87.1% and 60.4% of the follicles, respectively.
The combination of a GnRH agonist with antagonist completely prevented the flare-up effect and enhanced the protective effect of the ovary from cisplatin-induced gonadotoxicity in rats.
随着手术和化疗治疗的不断进步，许多肿瘤患者的生存期越来越长，甚至可以完全治愈。然而，广泛用于治疗多种类型癌症的含铂药物会导致月经紊乱和卵巢功能衰竭，进而导致不孕。迄今为止，促性腺激素释放激素（GnRH）激动剂（GnRHa）和拮抗剂（GnRHant）被报道通过抑制女性性腺轴来作为化疗的卵巢保护剂。然而，它们都有各自的缺点，限制了它们的使用。GnRHa 在给药后第一周会出现“flare-up 效应”，并且目前尚无长效 GnRHant 制剂。GnRHa 与 GnRHant 联合使用可能会预防 GnRHa 的 flare-up 效应，并迅速抑制女性性腺轴。几项样本量较小的临床研究得出了相互矛盾的结论。在这项严格控制的动物研究中，我们研究了 GnRHa 和 GnRHant 联合治疗的优势。
12 周龄大鼠分为六组：对照组、顺铂（CDDP）组、GnRHa 组、GnRHant 组、联合（短期）组和联合（长期）组。后四组给予曲普瑞林（1mg/kg·d，连用 14 天）、西曲瑞克（0.5mg/kg·d，连用 10 天）、曲普瑞林（1mg/kg·d，连用 10 天）联合西曲瑞克（0.5mg/kg·d，连用 10 天），长期组连用 10 天，短期组连用 3 天。对照组给予生理盐水（1ml/kg·d，连用 10 天）。然后，除对照组外，所有组均给予顺铂（1mg/kg·d，连用 10 天），对照组再给予 10 天生理盐水。采集血样检测血清雌二醇（E2）、促黄体生成素（LH）和促卵泡生成素（FSH）水平。药物治疗后还观察动情周期。最后，采集双侧卵巢进行组织学研究和卵泡计数。
我们观察到 GnRHa 治疗的大鼠出现了 flare-up 效应，但联合治疗组均未出现。顺铂组的正常周期性百分比从 0%增加到 GnRHa、GnRHant、联合（lng）和联合（sht）组的 25.0%、33.3%、66.7%和 41.7%。预处理用 GnRHa、GnRHant 和联合（lng）分别显著保护原始卵泡免受破坏，保留了 57.6%、63.4%、87.1%和 60.4%的卵泡。
GnRH 激动剂与拮抗剂联合使用完全预防了 flare-up 效应，并增强了对顺铂诱导的大鼠性腺毒性的卵巢保护作用。
