Chronic hypersecretion of luteinizing hormone in transgenic mice selectively alters responsiveness of the alpha-subunit gene to gonadotropin-releasing hormone and estrogens

Steroid hormones can act either at the level of the hypothalamus or the pit uitary to regulate gonadotropin subunit gene expression. However, their exa ct site of action remains controversial. Using the bovine gonadotropin alph a-subunit promoter linked to an expression cassette encoding the beta-subun it of LH, we have developed a transgenic mouse model where hypersecretion o f LH occurs despite the presence of elevated ovarian steroids. We used this model to determine how hypersecretion of LH could occur when steroid level s are pathological. During transition from the neonatal period to adulthood , the endogenous LH beta subunit gene becomes completely silent in these mi ce, whereas the alpha-directed transgene and endogenous cu-subunit gene rem ain active. Interestingly, gonadectomy stimulates expression of the endogen ous alpha and LH beta subunit genes as well as the transgene; however, only the endogenous LH beta gene retains responsiveness to 17 beta-estradiol an d GnRH. In contrast, LH levels remain responsive to negative regulation by androgen. Thus, alpha-subunit gene expression, as reflected by both the tra nsgene and the endogenous gene, has become independent of GnRH regulation a nd, as a result, unresponsive to estradiol-negative feedback. This process is accompanied by a decrease in estrogen receptor alpha gene expression as well as an increase in the expression of transcription factors known to reg ulate the alpha-subunit promoter, such as cJun and P-LIM. These studies pro vide in vivo evidence that estrogen-negative feedback on alpha and LH beta subunit gene expression requires GnRH input, reflecting an indirect mechani sm of action of the steroid. In contrast, androgen suppresses alpha-subunit expression in both transgenic and nontransgenic mice. This suggests that a ndrogens must regulate alpha-subunit promoter activity independently of GnR H. In addition to allowing the assessment of site of action of sex steroids on a-subunit gene expression, these studies also indicate that chronic exp osure of the pituitary to LH-dependent ovarian hyperstimulation leads to a heretofore-undescribed pathological condition, whereby normal regulation of alpha, but not LH beta, subunit gene expression becomes compromised.