性ホルモン受容体 : 基礎と臨床

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Sex hormone, an essential hormone in reproduction, acts upon the tissues through binding to its receptors. Thus, the study on the receptors is essential for understanding the reproductive processes, physiologically or pathologically. With the advent of molecular biology, receptorology in our field has rapidly developed. In this lecture, we presented our recent findings on the receptor and its gene expression, together with some brief overview on the development of the receptor study, basically or clinically. I. Basic study. 1) Methology: A specific and highly sensitive quantitative RT-PCR assay for measurment of the steroid hormone receptor (SHR) mRNA was developed. 2) Rat progesterone receptor (PR)cDNA, especially PR-BcDNA, was partially cloned. Using primers designed upon the cloned cDNA, two distinct different promoters was found to exist in PR-A and B gene expression in the rat. 3) Tissue specificity of gene expression of the SHRs in the central and perpheral tissues: The synthesis of the receptor protein was regulated mostly on the level of transcription. In some tissues, however, the receptor synthesis was regulated posttranscriptionally. Gene expression of the SHRs was widely distributed even in non-target tissue, indicating the existence of `basic action' of SH on the tissues. 4) Primate monkey studies: SHR, expecially PR, was localized mostly in the preoptic hypothalamic region and hypophysis in contrast with its wide distribution in the rat brain, suggesting the more limited feedback site of progesterone in women. 5) Brain sex differentiation and acquisition of steroid sensitivity: Region-specific and dynamic appearance of SHRs during peri- and postnatal development seemed to a major determinant of sex differentiation and hormone sensitivity' acquisition in female rats. Based upon analysis of PR-A and B mRNAs, gene expression of PR-B was first `turn on', followed by PR-B gene expression. Progesterone seemed to be associated with `termination' of the critical period of sex differentiation in the brain. 6) Thyroid hormone may be a regulator of synthesis and gene expression of the PR in rat cerebral cortex. Arachidonic acid, released from cell membrane, regulated SHRs in a non-competitive way, indicating some `second messenger' role. Cross-talk might exist between the membrane factor and SHR. 7) Antisense mRNA against GnRHmRNA, SH2RNA, was identified in rat brain. Most interestingly, there was a reciprocal relationship between GnRHmRNA and SH2RNA, suggesting some GnRHmRNA regulatory mechanism other than previously thought. 8) Depression of the GnRH receptor (GnRHR)mRNA level by GnRH agonist indicated another mechanism on down-regulation of GnRHR. II. Clinical study. 9) ER-B variant and infertity : The B-variant in leucocyte using the RT-PCR was not detected in the patients with abortion, confirming an artefact of `the B-variant' as recently reported. 10) SHR status in endometrial cancer (ED) : Although the receptors decreased with decreasing grades of histological differentiation, there was mismatch between the receptor and its mRNA, indicating regulation of the receptor synsthesis at both transcriptional and posttranscriptional level. Analysis of the SHR and survival rates revealed the value of the receptors as a significant prognostic factor. Incidences of the 4 subtype ECs based upon ER and PgR in Japanese were similar to those of other populations, which differed from those of the breast cancer subtypes. 11) Outlaw ER variant transcript, particularly the exon 7 deletion ER one, and gene expresseion of PgR isoforms A and B were for the first time detected and in some ECs existed at disproportional rates, suggesting the existence of the aberrant gene expression of the receptors, and further implying its involvement in carcinogenesis and/or progression of the cancer. (Supported by grants from the Ministry of Education, the Japan Foundation for Brain Research, Tokyo, and the Ogya Donation Fund, Tokyo)
1994-08-01

性ホルモン受容体 : 基礎と臨床

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