Recent advances in molecular techniques have led to the use of transgenic mice as a means to increase our understanding of physiologic systems and to mimic human diseases. The field of reproduction has benefited recently from the construction of animals with gene deletions such as estrogen receptor, mullerian inhibitory substance, and inhibin. We have examined another means of perturbing the reproductive axis-overexpression of the beta (β) subunit of luteinizing hormone (LH). Specifically, we asked two questions: (1) does targeted expression of a chimeric gonadotropin transgene lead to hypersecretion of pituitary LH, and (2) what is the impact of elevated serum LH upon reproductive function? To this end we generated 2 chimeric transgenes, each containing an alpha subunit promoter and an additional LHβ subunit gene. Two LHβ subunit genes were tested: wild-type bovine LHβ (bLHβ) and a long-acting bLHβ subunit containing the carboxyl terminal peptide (CTP) of the beta subunit of human chorionic gonadotropin (bLHβCTP), with the hope of obtaining mice with elevated serum LH. Targeted expression of either transgene led to markedly elevated LH levels in female transgenics. Expression of the bLHβ transgene in females led to moderately impaired fertility due to the development of mildly cystic ovaries and a prolonged luteal phase. In contrast, mice expressing the bovine LHβ-CTP gene had elevated sex steroids, ovulated infrequently, maintained a prolonged luteal phase, and developed pathologic ovarian changes such as cyst formation, stromal cell abnormalities, and granulosa cell tumors. Further study demonstrated that this phenotype was established prior to puberty.
Remarkably, the expression of the transgenes had a much different impact on transgenic male mice. Despite pituitary expression of the transgenes, serum LH was not elevated. Further analysis demonstrated repression of the endogenous mouse LHβ gene and differential regulation of the transgene. Interestingly, both bLHβ and bLHβCTP males demonstrated reduced testicular weights, presumably as a result of reduced serum FSH levels.
These studies demonstrate sex specific differences in the maintenance of reproductive homeostasis, illustrate the adverse effect of chronically elevated LH, and suggest that a short-acting LH may be critical for normal functioning of the ovary.