Targeted disruption of LH receptor gene revealed the importance of uterine LH signaling

Numerous previous studies have demonstrated that LH and hCG can directly regulate several uterine functions. We investigated in the present study, whether uterine phenotype in LH receptor knockout animals resulted also from the absence of direct actions of LH in the uterus. The phenotype consisted of marked growth reduction of uterus, decreased thickness of endometrial and myometrial layers, number of endometrial glands, height of luminal epithelium and vascular space. Analysis of uterine gene expression by mouse genome U74Av2 Affymetrix genechips revealed a differential expression of 155 genes by more than 3-fold (range 3-53-fold) between null and wild-type animals. Of these, 89 genes decreased and 66 increased in uterus of null animals. Semi-quantitative RT-PCR confirmed the differential expression of several selected genes. The decreased genes can be clustered into 18 functional families and the increased into 15 functional families. Semi-quantitative RT-PCR, Western blotting and immunocytochemistry demonstrated a decreased expression of ERβ, PR-A, PR-B and AR in uterus of null animals as compared with wild-type siblings. Twenty-one-day estradiol and progesterone replacement therapy did not normalize the decrease in the number of endometrial glands and several genes that either decreased or increased in expression. The partial success of therapy suggests that direct LH actions could be required to completely normalize the uterus. In summary, findings on the knockout model reaffirm that LH and hCG control uterine functions directly as well as indirectly through increasing ovarian synthesis of steroid hormones and both actions are required for normal uterine biology.