estrone-sulfate and Endometrial-Hyperplasia

The identification of genes and pathways that are affected by estrogenization may shed light on the mechanisms of estrogen action. Here, we describe the expression pattern of a novel estrogen-induced gene, EIG121, in distinct types of endometrial cancer.. EIG121 was identified by cDNA microarray analysis of endometrial RNA from women receiving either placebo or estrogen replacement therapy. The expression level of EIG121 was then measured by real-time quantitative reverse transcription-PCR in benign, hyperplastic, and malignant endometrial samples. A polyclonal antibody was used to detect EIG121 protein by immunohistochemistry.. In postmenopausal endometrium, estrogen replacement therapy with Premarin and synthetic estrogen sulfate conjugates induced the expression of EIG121 2- and 3-fold, respectively. In premenopausal endometrium, the expression of EIG121 was higher in the estrogen-dominated proliferative phase than the secretory phase. In endometrial complex, hyperplasia, and endometrioid adenocarcinoma, neoplastic proliferations associated with estrogen excess, the expression of EIG121 was significantly elevated (on average 3.8-fold in hyperplasias and 21-fold in grade 1 tumors). Although the level of EIG121 mRNA in grade 3 endometrioid carcinoma was still 3.5-fold of that in benign endometrium, EIG121 expression tended to decline with increasing tumor grade and disease stage. Immunohistochemistry showed faint staining of normal endometrial epithelium, but intense staining of endometrioid tumors. In sharp contrast, EIG121 expression was significantly suppressed in both uterine papillary serous carcinoma and uterine malignant mixed mullerian tumor, two tumors not associated with estrogen exposure, to <5% of the level in benign endometrium.. Our results suggest that EIG121 is a good endometrial biomarker associated with a hyperestrogenic state and estrogen-related type I endometrial adenocarcinoma.

Topics: Adenocarcinoma; Biomarkers, Tumor; Case-Control Studies; Endometrial Hyperplasia; Endometrial Neoplasms; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Estrone; Expressed Sequence Tags; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Membrane Proteins; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The present study was undertaken to assess in vitro the endometrial extraction of natural estrogens. Normal, hyperplastic, and neoplastic endometria were studied. This was accomplished by the use of double isotope, single-injection techniques performed during the extracorporeal perfusion of human isolated uterus. The differential permeability of vascular beds in normal and neoplastic endometrium to estrogens was evaluated. The effects of binding by human serum proteins on estrogen influx into the endometrium were also determined. When protein-free Ringer's solution was used as an injection vehicle, both normal and abnormal endometrium permitted free diffusion of estradiol (E2), estrone (E1), and estrone sulfate (E1S). In contrast, the endometrial extraction of these estrogens from human female serum was significantly lower than that obtained with Ringer's solution. The extraction of E2, E1, and E1S from human serum was significantly higher in hyperplastic and carcinomatous endometria than in normal proliferative endometria. We conclude that 1) membrane permeability to estrogenic influxes differs between normal and abnormal endometria and 2) plasma proteins decrease the endometrial uptake of estrogens.

Topics: Adenocarcinoma; Endometrial Hyperplasia; Endometrium; Estradiol; Estrone; Female; Humans; Perfusion; Uterine Neoplasms; Uterus

Exogenous oestrogens are highly effective in relieving not only the acute symptoms of ovarian failure, such as vasomotor instability and vaginal dryness, but also in conserving postmenopausal bone mass. However, the oestrogen doses needed to achieve these benefits also induce endometrial proliferation. The risk of endometrial hyperplasia and carcinoma are thereby increased and unopposed oestrogen therapy is associated with a high incidence of abnormal vaginal bleeding requiring appropriate, invasive investigations. The cost-effectiveness of therapy and patient compliance are likely to be correspondingly reduced. Various strategies have been proposed to try to overcome the risk of endometrial hyperstimulation and these strategies have been reviewed. Based upon the available evidence, progestogen addition appears the most sensible and has been shown to be effective. It is now clear that progestogens should, in sequential therapies, be administered for 12 days each cycle for maximum protection. Concern has been expressed that the regular withdrawal bleed induced by sequential treatment will reduce patient compliance. Progestogens have, therefore, been added in a continuous fashion to try to prevent endometrial proliferation and thereby induce amenorrhoea. The ideal continuous, oestrogen/progestogen regimen has not yet been developed: all those evaluated to date are associated with a high incidence of breakthrough bleeding which is likely to restrict their use. Progestogens can cause undesirable physical, psychological and metabolic effects. The incidence and severity of side-effects will depend upon the type of progestogen prescribed, the route of administration, and the dose. Minimum effective daily doses of certain types of progestogens have now been established in terms of endometrial protection. Regrettably, few data are available on the physical and psychological effects of these progestogen doses: more information is available on lipid and lipoprotein effects but the data are confused and, at times, contradictory. More research is urgently needed to determine which of these progestogens is most suitable for addition to postmenopausal oestrogen therapy.

Topics: Endometrial Hyperplasia; Estradiol; Estriol; Estrogens; Estrogens, Conjugated (USP); Estrone; Female; Humans; Menopause; Progestins; Retrospective Studies; Risk; Uterine Neoplasms

The properties of estrone (E1) and dehydroepiandrosterone (DHEA) sulfatase activities are reported. Endometrial biopsy specimens were obtained using a Novak curette. Cycle stage was assessed from histological dating of endometrium, plasma estradiol and progesterone levels, and patient history. Both sulfatases are membrane-bound enzymes. The optimum pHs in Tris-HCl buffer were 6.5 for E1 sulfatase and 7.3 for DHEA sulfatase. Lowest activities and different optimum pHs were obtained with imidazole, maleate, or acetate buffers. DHEA sulfatase is more sensitive to thermal inactivation than E1 sulfatase. From kinetic studies, apparent Km values of 3.1 microM for E1 sulfatase and 5.7 microM for DHEA sulfatase were calculated. Noncompetitive inhibition of E1 sulfatase by DHEA sulfate and of DHEA sulfatase by E1 sulfate were demonstrated. The effects of inorganic ions and unconjugated steroids were also tested. These results are consistent with two different activities hydrolyzing E1 or DHEA sulfates. Neither activity varies during normal menstrual cycles nor is not correlated to plasma progesterone or 17 beta-estradiol levels. An isolated increase in E1 sulfatase occurred in the proliferative phase of irregular menstrual cycles, postantibiotic-treated salpingitis, or hyperplastic endometrium.

Topics: Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Endometrial Hyperplasia; Endometrium; Estrone; Female; Hot Temperature; Humans; Hydrogen-Ion Concentration; Kinetics; Menstruation; Salpingitis; Steryl-Sulfatase; Subcellular Fractions; Sulfatases; Uterine Diseases