Inhibitory Effects of a Sustained Release Formulation of the Gonadotrophin-Releasing Hormone Agonist on Reproductive Function in the Dog

研究了一种促性腺激素释放激素激动剂（GnRH-A）缓释制剂对犬生殖功能的抑制作用，得到了以下结果。一种敏感和特异性的酶免疫分析法用于测定GnRH使用单克隆抗体已经开发。该方法成功地应用于下丘脑和血浆GnRH的分析。在雄性狗中，下丘脑GnRH水平随着年龄的增长而增加，直到4个月，然后从6个月到2岁下降到平稳期。5只成年雄性犬静脉注射合成GnRH后，血浆水平降低50%所需的时间为2.2(]SY.+- [)0.1 (SEM) min。犬睾丸黄体生成素（LH）受体的发育与睾丸生长和血浆雄激素的增加一致。性腺对黄体生成素敏感性的增加可能是雄性犬在青春期雄激素分泌显著增加的原因。单次注射GnRH-A缓释制剂（1 mg肽/kg）可抑制雄性犬垂体-睾丸功能。治疗4个月后，观察到精子发生完全恢复正常。在体外灌注实验中，连续输注GnRH (10 nM) 4小时，观察到垂体脱敏，提示药物的长效效力可能是抑制垂体和睾丸功能的原因。母狗产后4个月内开始多次注射GnRH-A缓释制剂（肽1 mg /kg，每3个月1次）治疗9个月，未见新发发情。与此相反，母鼠产后5个月单次注射GnRH-A缓释制剂（0.1 mg肽/kg）可引起诱导热，此时母鼠交配，产仔正常。

Inhibitory effects of a sustained release formulation of the gonadotrophin-releasing hormone agonist (GnRH-A) on reproductive function in the dog were examined, and the following results were obtained.1. A Sensitive and specific enzyme immunoassay for the determination of GnRH using a monoclonal antibody has been developed. This method was successfully applied for analysis of hypothalamic and plasma GnRH.In male dogs, hypothalamic GnRH levels increased with age up to 4 months, then fell to a plateau from 6 months to 2 years. The time required for a 50% reduction in plasma levels following intravenous administation of synthetic GnRH to 5 adult male dogs was 2.2(]SY.+-。[)0.1 (SEM) min.2. The development of testicular luteinizing hormone (LH) receptors in the dog was coincident with the increase in testicular growth and plasma androgens. The increase in gonadal sensitivity to LH could be reponsible for the marked increase in secretion of androgen which occurs during puberty in the male dog.3. A single injection of sustained-release formulation of GnRH-A (1 mg peptide/kg) could inhibit pituitary-testicular function in the male dog. Four months after the treatment, a complete return to normal spermatogenesis was observed. When exposed to a 4-h continuous infusion of GnRH (10 nM), pituitary desnsitization was observed in in vitro perifusion experiments, suggesting that the long-acting potency of the drug could be the reason for the inhibition of the pituitary and testicular function.4. During 9 months of treatment with multiple injections of sustained-release formulation of GnRH-A (1 mg peptide/kg, once every 3 months), starting within 4 months postpartum in bitches, no new oestrus was detected. On the contrary, a single injection of sustained-release formulation of GnRH-A (0.1 mg peptide/kg) at 5 months postpartum in bitches resulted in an induced heat : the bitches mated at those time and produced normal litters.