Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue.

Many peripheral reproductive tissues have been found to contain gonadotrophin-releasing hormone (GnRH) and express the GnRH gene at low levels, presumably because the hormone functions in a paracrine/autocrine fashion. This study was designed to investigate and characterize GnRH gene expression in human endometrial tissue at different stages of the endometrial cycle. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis together with Southern blot assay demonstrated that human endometrial tissue expresses the proGnRH gene. RNA samples from endometrial tissue were analysed with two pairs of oligonucleotide primers. Both gave a doublet 870 bases apart at the expected sizes, indicating that both the upstream and downstream transcriptional start sites of the GnRH gene are used in endometrial tissue and that transcripts with and without intron 1 were produced. Our data also demonstrated that utilization of the two promoters varies with the stage of the endometrial cycle. The largest difference came from the mRNA transcribed from the downstream promoter and without intron 1. This mRNA was expressed at a very low level during the proliferative phase and dramatically increased almost 10-fold (P < 0.01) during the early secretory phase, and subsequently decreased 5-fold during the late secretory stage. The presence of GnRH mRNA in the endometrium, as well as the differential expression of the GnRH gene during the early secretory phase provides physiological evidence that human GnRH may play a paracrine/autocrine function in the human uterus.

Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis.

UNLABELLED: Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules. METHODS: Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule-in-nodule lesions. Five nodule-in-nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA-LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule-in-nodule lesions were assessed separately from the background macroregenerative nodule. RESULTS: 4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA-LIs lower than the mean of surrounding cirrhotic nodules. All nodule-in-nodule lesions, whether atypical or overtly malignant, had PCNA-LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA-LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma. CONCLUSION: Macroregenerative nodules derive neither their size nor their premalignant potential from on-going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development.