Miki Nishigaki

Expression of Progesterone Receptor Form A and B mRNAs in Gynecologic Malignant Tumors

This study was designed to examine the biological implication of progesterone receptor (PR) forms A and B mRNA expressions in gynecologic cancers. The ratio of PR form A to form B in mRNA expression was approximately 1:1 in all endometria studied. The predominant expressions of form B transcript occurred in 6 out of 7 cases of advanced stages (stages III and IV) in ovarian cancers, in 5 out of 9 cases of cervical cancers, and in 5 out of 11 cases of endometrial cancers. In conclusions, the dominancy of PR form B mRNA expression might be associated with the expression of a malignant phenotype in gynecologic cancers, and advanced clinical stage in ovarian cancers, suggesting a biological marker of malignant phenotype in these three types of cancer cell.

The effect of estrogen and androgen on androgen receptors and mRNA levels in uterine leiomyoma, myometrium and endometrium of human subjects

This study was designed to show the effect of estrogen and androgen on the level of testosterone and dihydrotestosterone specific binding sites (TBS and DHTBS, respectively) and to clarify the implication of androgen receptor mRNA expression to TBS and DHTBS in human uterine tissues. Estrogen mainly induces the increase of TBS and androgen receptor mRNA in uterine endometrium and leiomyoma. TBS increased by estrogen are downregulated when testosterone is given along with estrogen, while androgen receptor mRNA increased by estrogen was not significantly altered by testosterone with estrogen in endometrium and leiomyoma. These results suggest that the androgen receptor mRNA determined might encode TBS and that testosterone may stimulate the metabolic rate of TBS, or inhibit the translation rate of androgen receptor mRNA to TBS. Furthermore, the biological character of leiomyoma is considered to be an endometrial type.

Tissue Differences in the Expression of mRNAs of Ha-ras, c-myc, fos and jun in Human Uterine Endometrium, Myometrium and Leiomyoma under the Influence of Estrogen/Progesterone

Ha-ras expression level in uterine endometrium (EM) in the proliferative phase (PP) was significantly higher than that in the secretory phase (SP). c-myc expressions were detected in EM, uterine myometrium (MM) and uterine leiomyoma (LM) without any cyclic change; fos expressions in LM, MM, and EM were detectable in PP, but not in SP. jun expression level in LM was significantly higher than that in MM and EM in PP, but did not alter during the menstrual cycle. Estrogen elevated the levels of Ha-ras and fos mRNAs in the three tissues, jun mRNA in MM and EM, and c-myc mRNA in LM and MM. These results suggest that there is a tissue difference in the expression of Ha-ras, c-myc, fos and jun among EM, MM and LM, under the influence of estrogen/progesterone.

Biological implications of estrogen and androgen effects on androgen receptor and its mRNA levels in human uterine endometrium

It has been shown that some effects of testosterone are different from those of its 5 alpha-reduced metabolite, dihydrotestosterone. Briefly, activities of testosterone might be related to cellular differentiation, whereas dihydrotestosterone acts on cellular proliferation. The number of testosterone binding sites in the uterine endometrium was increased by estradiol dipropionate, and this increase was down-regulated by testosterone cypionate. Dihydrotestosterone-specific binding sites in the endometrium were not modulated by estradiol dipropionate and testosterone cypionate. The dissociation constants of the binding sites for testosterone and dihydrotestosterone were not altered by these steroids. Estradiol dipropionate with or without testosterone cypionate induced androgen receptor mRNA expression in the endometrium. In conclusion, testosterone might predominantly affect cellular differentiation in the endometrium.

Expression of Aberrant Estrogen Receptor mRNA in Endometrial Cancers in Comparison with Normal Endometria

In endometrial cancers, some overexpression of estrogen receptor (ER) mRNA occurred in comparison with the ER mRNA level in normal endometria. DNA binding domains (DBDs) of ER mRNA were detected in 100% (13/13) of the endometrial cancers, and a mutated ER-DBD mRNA was found in 3 of the 13 by S1 nuclease protection analysis. It is suggested that estrogen might lead to disorder in the promotion of estrogen-inducible proteins in these 3 endometrial cancers, which seem to have a point-mutated DBD of the ER and a functional steroid-binding domain, resulting in the dedifferentiation of the original cells, and that the development and growth of cancer cells might, in part, be driven by estrogen.

Danazol decreases transcription of estrogen receptor gene in human monocytes

1. Administration of danazol for over one month reduced the levels of estrogen receptor (ER) and its mRNA to approximately 50 and 20%, respectively in monocytes. 2. Danazol did not alter the degradation rate of ER mRNA in monocytes. 3. Danazol decreased the transcription rate of ER gene to approximately 50% in monocytes in a run-on assay. 4. Danazol may release estrogen predominance via the reduction of transcription for ER gene, which leads to the reduction of ER mRNA and ER expressions in monocytes.

Effects of estradiol and testosterone on the synthesis, expression and degradation of androgen receptor in human uterine endometrial fibroblasts

The mechanism of known receptor-mediated androgen effects on the endometrial stroma was studied in endometrial fibroblasts derived from human uterus. 17beta-Estradiol (E) induced the expressions of androgen receptor (AR) mRNA, and predominantly increased the level of testosterone-binding sites (TBS) in uterine endometrial fibroblasts. The effect on the level of dihydrotestosterone-binding sites (DHTBS) was similar but smaller. This result suggests that the AR mRNA expressed might encode TBS, but probably not DHTBS. The TBS level increased by estrogen was down-regulated by testosterone (T) + E, but the AR mRNA expression increased by E was not down-regulated by E + T in the fibroblasts. Although the synthesis rate of AR was slightly increased (p < 0.05) by E alone or E + T, the degradation rate of AR was significantly accelerated (p < 0.05) by E + T in the fibroblasts. This result suggests that T might stimulate the metabolic rate of TBS, but does not inhibit the synthesis rate of AR mRNA to TBS in endometrial fibroblasts. Copyright 1995 S. Karger AG, Basel

Effects of danazol and medroxyprogesterone acetate on estrogen-(estradiol and estriol) specific binding sites in rabbit uterus

In rabbit uterus, the presence of separate specific binding sites for not only estradiol but also estriol has been proposed. These sites may be correlated with an antiestradiol effect. Therefore, this study was designed to investigate the effect of antiestrogenic agents such as danazol and medroxyprogesterone acetate (MPA), especially on the estriol binding sites. Danazol and MPA in combination with estradiol were administered subcutaneously to immature female rabbits daily for 10 days, and resulted in a significant (p < 0.05) decrease in uterine weight and estradiol binding sites in the uterus. Treatment with MPA significantly (p < 0.05) decreased the level of estriol binding sites, but treatment with danazol resulted in this to a minimal extent in the uterus primed by estradiol. MPA did not bind to estradiol and estriol binding sites, while danazol at a high concentration bound to estriol binding sites with some affinity, but not to estradiol binding sites in the uterine cytosol of estrogen-primed rabbits. These results suggest that within the antiproliferative effect of danazol and MPA (an antiestrogenic action on estrogen-stimulated uterine growth) there are likely to be specific differences between some of the possible mechanisms of danazol and MPA in their action at the estriol binding site.