Risma K A, Clay C M, Nett T M, Wagner T, Yun J, Nilson J H
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1322-6. doi: 10.1073/pnas.92.5.1322.
Hypersecretion of luteinizing hormone (LH) is implicated in infertility and miscarriages in women. A lack of animal models has limited progress in determining the mechanisms of LH toxicity. We have recently generated transgenic mice expressing a chimeric LH beta subunit (LH beta) in gonadotropes. The LH beta chimera contains the C-terminal peptide of the human chorionic gonadotropin beta subunit. Addition of this peptide to bovine LH beta resulted in a hormone with a longer half-life. Furthermore, targeted expression of the LH beta chimera led to elevated LH levels and infertility in female transgenics. These mice ovulated infrequently, maintained a prolonged luteal phase, and developed pathologic ovarian changes such as cyst formation, marked enlargement of ovaries, and granulosa cell tumors. Testosterone and estradiol levels were increased compared to nontransgenic littermates. An unusual extragonadal phenotype was also observed: transgenic females developed hydronephropathy and pyelonephritis. The pathology observed demonstrates a direct association between abnormal secretion of LH and infertility and underscores the utility of the transgenic model for studying how excess LH leads to cyst formation, ovarian tumorigenesis, and infertility.
促黄体生成素（LH）分泌过多与女性不孕和流产有关。缺乏动物模型限制了在确定LH毒性机制方面的进展。我们最近培育出了在促性腺激素细胞中表达嵌合LHβ亚基（LHβ）的转基因小鼠。LHβ嵌合体包含人绒毛膜促性腺激素β亚基的C末端肽。将该肽添加到牛LHβ中产生了一种半衰期更长的激素。此外，LHβ嵌合体的靶向表达导致雌性转基因小鼠LH水平升高和不孕。这些小鼠排卵不频繁，黄体期延长，并出现病理性卵巢变化，如囊肿形成、卵巢明显肿大和颗粒细胞瘤。与非转基因同窝小鼠相比，睾酮和雌二醇水平升高。还观察到一种不寻常的性腺外表型：转基因雌性小鼠出现肾积水和肾盂肾炎。观察到的病理学表现证明了LH异常分泌与不孕之间的直接关联，并强调了转基因模型在研究过量LH如何导致囊肿形成、卵巢肿瘤发生和不孕方面的实用性。
