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Chronic Hypersecretion of Luteinizing Hormone in Transgenic Mice Selectively Alters Responsiveness of the -Subunit Gene to Gonadotropin-Releasing Hormone and Estrogens

Department of Pharmacology (R.A.A., R.K.A., J.H.N.) Department of Biostatistics (J.S.R.) Case Western Reserve University Cleveland, Ohio 44106
Animal Reproduction and Biotechnology Laboratory (T.M.N.) Colorado State University Fort Collins, Colorado 80523

Steroid hormones can act either at the level of the hypothalamus or the pituitary to regulate gonadotropin subunit gene expression. However, their exact site of action remains controversial. Using the bovine gonadotropin -subunit promoter linked to an expression cassette encoding the ß-subunit of LH, we have developed a transgenic mouse model where hypersecretion of LH occurs despite the presence of elevated ovarian steroids. We used this model to determine how hypersecretion of LH could occur when steroid levels are pathological. During transition from the neonatal period to adulthood, the endogenous LHß subunit gene becomes completely silent in these mice, whereas the -directed transgene and endogenous -subunit gene remain active. Interestingly, gonadectomy stimulates expression of the endogenous and LHß subunit genes as well as the transgene; however, only the endogenous LHß gene retains responsiveness to 17ß-estradiol and GnRH. In contrast, LH levels remain responsive to negative regulation by androgen. Thus, -subunit gene expression, as reflected by both the transgene and the endogenous gene, has become independent of GnRH regulation and, as a result, unresponsive to estradiol-negative feedback. This process is accompanied by a decrease in estrogen receptor gene expression as well as an increase in the expression of transcription factors known to regulate the -subunit promoter, such as cJun and P-LIM. These studies provide in vivo evidence that estrogen-negative feedback on and LHß subunit gene expression requires GnRH input, reflecting an indirect mechanism of action of the steroid. In contrast, androgen suppresses -subunit expression in both transgenic and nontransgenic mice. This suggests that androgens must regulate -subunit promoter activity independently of GnRH. In addition to allowing the assessment of site of action of sex steroids on -subunit gene expression, these studies also indicate that chronic exposure of the pituitary to LH-dependent ovarian hyperstimulation leads to a heretofore-undescribed pathological condition, whereby normal regulation of , but not LHß, subunit gene expression becomes compromised.

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