Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors.
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.
Risma
K A
KA
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Clay
C M
CM
Nett
T M
TM
Wagner
T
T
Yun
J
J
Nilson
J H
JH
D000818:Animals; D006063:Chorionic Gonadotropin / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006869:Hydronephrosis / Q000209:etiology; D007246:Infertility / Q000235:genetics; D007668:Kidney / Q000473:pathology; D007986:Luteinizing Hormone / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008822:Mice, Transgenic; D010048:Ovarian Cysts / Q000209:etiology; D010051:Ovarian Neoplasms / Q000209:etiology; D010053:Ovary / Q000473:pathology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins
D006063:Chorionic Gonadotropin; D011993:Recombinant Fusion Proteins; D007986:Luteinizing Hormone