Scott I S, Bennett M K, Porter-Goff A E, Harrison C J, Cox B S, Grocock C A, O'Shaughnessy P J, Clayton R N, Craven R, Furr B J
Geoffrey Harris Laboratory, Department of Human Anatomy, University of Oxford, U.K.
J Mol Endocrinol. 1992 Jun;8(3):249-58. doi: 10.1677/jme.0.0080249.
Hypogonadal (hpg) mutant mice, with a congenital deficiency of hypothalamic gonadotrophin-releasing hormone (GnRH), and testicular feminized (tfm) mice, which lack a functional androgen receptor, were used to study the effects of the potent GnRH agonist 'Zoladex' (ICI 118630; D-Ser (Bu(t))6, Azgly10-GnRH) on pituitary and gonadal function. Zoladex (0.5 mg) in a sustained-release lactide-glycolide copolymer depot was administered subcutaneously under anaesthesia and was left in place for 7 days, after which time the effects of the drug upon pituitary and serum gonadotrophin concentrations, glycoprotein hormone subunit mRNAs and testicular morphology were investigated. At the pituitary level, Zoladex treatment resulted in a substantial reduction in LH content in normal males, and LH content was depressed in hpg mice even below the basal levels normally found in these mutants. Pituitary LH content in the Zoladex-treated animals was depressed in the tfm groups, but not to the same levels as those found in the normal and castrated normal mice. Zoladex treatment at the time of castration prevented the post-operative elevation in serum LH associated with castration alone. In the androgen-deficient tfm mouse, Zoladex did not depress the normally elevated serum LH levels. Serum LH in the hpg animals was, in all cases, below the limit of detection of the assay. Pituitary FSH content was depressed into the hpg range in both the normal and castrated animals, but there was no further depression in the hpg mice. The pituitary content was reduced in the tfm mice, again the effects not being as dramatic as in the normal and castrated animals. Serum FSH content, as measured by radioimmunoassay, was depressed by 50% in normal mice; there was no reduction in the hpg mice, however. With regard to pituitary gonadotrophic hormone gene expression, Zoladex administration to normal mice caused a dramatic reduction in LH beta mRNA content, to a level approximating that found in untreated hpg mice. The drug also depressed LH beta mRNA in the castrated group to the hpg range when given at the time of castration, whereas in untreated castrated mice there was a significant increase in LH beta mRNA. In the tfm mouse, which can be considered as a model for long-term failure of androgen feedback, Zoladex again induced a fall in LH beta mRNA, but not to the same extent as in the normal and normal castrated group. Zoladex had no effect on the already low levels of LH beta mRNA found in hpg mice.(ABSTRACT TRUNCATED AT 400 WORDS)
性腺功能减退（hpg）突变小鼠先天性缺乏下丘脑促性腺激素释放激素（GnRH），而睾丸雌性化（tfm）小鼠缺乏功能性雄激素受体，利用这两种小鼠研究强效GnRH激动剂“诺雷德”（ICI 118630；D-丝氨酸（叔丁基）6，丙氨酰10-GnRH）对垂体和性腺功能的影响。在麻醉状态下，将含0.5毫克诺雷德的缓释丙交酯-乙交酯共聚物长效注射剂皮下给药，并留置7天，之后研究该药物对垂体和血清促性腺激素浓度、糖蛋白激素亚基mRNA以及睾丸形态的影响。在垂体水平，诺雷德治疗使正常雄性小鼠的促黄体生成素（LH）含量大幅降低，hpg小鼠的LH含量甚至低于这些突变体通常的基础水平。诺雷德处理的动物中，tfm组的垂体LH含量降低，但未降至正常和去势正常小鼠的水平。去势时给予诺雷德可防止仅去势后血清LH的术后升高。在雄激素缺乏的tfm小鼠中，诺雷德并未降低通常升高的血清LH水平。hpg动物的血清LH在所有情况下均低于检测限。正常和去势动物的垂体促卵泡生成素（FSH）含量均降至hpg范围，但hpg小鼠未进一步降低。tfm小鼠的垂体含量降低，同样，其影响不如正常和去势动物显著。通过放射免疫测定法测得，正常小鼠的血清FSH含量降低了50%；然而，hpg小鼠的血清FSH含量未降低。关于垂体促性腺激素基因表达，给正常小鼠注射诺雷德导致LHβ mRNA含量大幅降低，降至未处理hpg小鼠的水平。在去势时给予该药物，去势组的LHβ mRNA也降至hpg范围，而未处理的去势小鼠中LHβ mRNA显著增加。在可被视为雄激素反馈长期失效模型的tfm小鼠中，诺雷德再次导致LHβ mRNA下降，但程度不如正常和正常去势组。诺雷德对hpg小鼠中已很低的LHβ mRNA水平没有影响。（摘要截选至400字）
