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Overexpression of Human Chorionic Gonadotropin Causes Multiple Reproductive Defects in Transgenic Mice¹

Departments of Pathology,³ Molecular and Cellular Biology,⁴ Molecular and Human Genetics,⁵ Baylor College of Medicine, Houston, Texas 77030

Human CG is a pregnancy marker secreted by the placenta, and it utilizes the same receptors as does LH. Human CG is a heterodimer, and its subunits are expressed in tissues other than placenta. Similarly, LH/hCG receptors are also expressed in multiple tissues; however, the physiological significance of this expression is unknown. Free hCGß is efficiently secreted in vitro in transfected cells and is highly expressed in many human cancers; however, the biological effects of free hCGß in vivo are unknown. To study in vivo consequences of elevated levels of free hCGß and hCG dimer in both male and female reproductive physiology, we used mouse metallothionein 1 promoter to generate multiple lines of transgenic mice that overexpressed either one or both subunits of hCG. Although mice expressing the glycoprotein hormone subunit are normal and fertile, both male and female transgenic mice overexpressing only the hormone-specific hCGß subunit are infertile. The hCGß subunit-expressing transgenic female mice progressively develop cystic ovaries, whereas the male transgenic mice are infertile but otherwise are not phenotypically discernible. In contrast, both the male and female transgenic mice coexpressing high levels of the hCG subunits (i.e., the hCG dimer) demonstrate multiple reproductive defects. The male transgenic mice have Leydig cell hyperplasia, very high levels of serum testosterone, reduced testis size, and dramatically enlarged seminal vesicles and are infertile and display overly aggressive behavior when caged with females. The female transgenic mice are also infertile, have elevated levels of serum estradiol, and progressively develop hemorrhagic and cystic ovaries with thecal layer enlargement and stromal cell proliferation and degenerating kidneys. These results suggest that the in vivo biological effects of ectopically expressed free hCGß subunit are distinct from those of the hCG dimer and are gender specific. These transgenic mice are useful models for studying the biology of free hCGß subunit, for further analyzing the gain of function effects of hCG during early Leydig cell development, and for studying the roles of hCG in ovarian and kidney pathophysiology and function.

¹ These studies were supported in part by funds (to T.R.K.) from the Moran Foundation (Department of Pathology, Baylor College of Medicine) and by NIH grant CA 60651 and Specialized Cooperative Centers Program in Reproduction Research grant HD-07495 (to M.M.M.). The Hormone Assay Core at the University of Virginia is supported by an NIH grant (U54-HD28-934) to the Center for Cellular and Molecular Studies in Reproduction.

² Correspondence: T. Rajendra Kumar, Department of Pathology, Baylor College of Medicine, Houston, TX 77030. FAX: 713 798 7505; tkumar{at}bcm.tmc.edu

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