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Endometrium of hormone-treated postmenopausal women

ABSTRACT: Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

ORGANISM(S): Homo sapiens

PROVIDER: GSE12446 | GEO | 2008/08/21

SECONDARY ACCESSION(S): PRJNA113003

REPOSITORIES: GEO

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Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labbeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References:; Klaassens et al., 2006; Hanifi-Moghaddam et al., 2007; Verheul et al., 2007 Experiment Overall Design: This study was designed as a controlled clinical trial. Patients who visited our clinics to undergo vaginal hysterectomy for treatment of prolapse, were eligible to participate in this study. The trial was performed in the period before the scheduled surgery. After informed consent, the patients were sequentially assigned to one of the following treatment groups: Experiment Overall Design: - Control-group (no hormonal treatment); Experiment Overall Design: - Tibolone-group (2.5 mg tibolone (Livial, N.V. Organon, Oss, The Netherlands) administered orally every day, starting 21 days prior to surgery); Experiment Overall Design: - E2 group (2 mg of estradiol administered orally every day, starting 21 days prior to surgery); Experiment Overall Design: - E2+MPA-group (2 mg estradiol + 5 mg MPA administered orally every day, starting 21 days prior to surgery). Experiment Overall Design: Pure endometrium was isolated and used for profiling. 31 samples, 3 of which were duplicates, were analyzed.

Project description:Use of long-acting progestin-only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understand the mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+progesterone (P4) were analyzed by q-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depo-Provera (Depo) treated women (n=6) and ovariectomized guinea pigs (GPs; n=12) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67-gene group regulated by all three progestins, whereas a 235-gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as an upstream regulator of the 235 LAPCMPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both LAPCsMPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-Depo versus pre-Depo administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. LAPC MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting feeds back to inhibit PR- and GR-mediated transcription. The resultant PR- and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.

Project description:Purpouse: Aims of this study were (1) to characterize the endometrial transcriptome, (2) to identify functional pathways, and (3) to molecularly characterize selected pathways overrepresented in the endometrium of day 7 post-ovulation induction of cows treated to ovulate larger versus smaller follicles Methods: Seventy-four multiparous, nonlactating, presynchronized Nelore cows received a progesterone-releasing device and estradiol benzoate on Day–10 (D?10). Animals received cloprostenol (large follicle-large CL group; LF-LCL; N = 35) or not (small follicle-small CL group; SF-SCL; N = 39) on D?10. Progesterone devices were withdrawn and cloprostenol administered 42 to 54 hours (LF-LCL) or 30 to 36 hours (SF-SCL) before GnRH treatment (D0). Tissues were collected at slaughter on D7. Transcriptional profiling of the endometrial tissue was performed by RNA-seq and protein markers for proliferation and apoptosis were identified by immunohistochemistry. Results: Functional enrichment data indicated that LF-LCL endometrium expressed greater abundance of genes associated with biosynthetic and metabolic processes, whereas SF-SCL endometrium .gene expression profile was biased towards cell proliferation. Extracellular matrix-related genes were also upregulated in the SF-SCL endometrium suggesting reorganization of the ECM towards a proliferation permissive phenotype. Immunohistochemistry data confirmed the greater proliferative activity observed in SF-SCL endometrium I comparison to LF-LCL counterparts, and indicated a time-related transition within experimental group. In conclusion, the periovulatory endocrine milieu regulates bovine endometrial gene expression. Furthermore, timing and amplitude of ovarian steroid secretion pattern seem to determine the transition from a proliferation permissive to a biosynthetic and metabolically active endometrial phenotype, which may be associated with the preparation of an optimally receptive uterine environment. Conclusion: the periovulatory endocrine milieu affected D7 endometrial molecular signature. Main pathways affected were related to cell proliferation, ECM composition and remodeling, biosynthetic and metabolic processes. Reported data further suggest that the endometrial tissue from LF-LCL cows experienced an early proliferative phase (D4), whereas the SF-SCL endometrium, exposed to a distinct periovulatory endocrine environment, expressed a delayed onset of the proliferative activity (D7). endometrial mRNA profiles of endocrine manipulated cows were generated by deep sequencing using Illumina HiScanSQ platform

Project description:Purpouse: Aims of this study were (1) to characterize the endometrial transcriptome, (2) to identify functional pathways, and (3) to molecularly characterize selected pathways overrepresented in the endometrium of day 7 post-ovulation induction of cows treated to ovulate larger versus smaller follicles Methods: Seventy-four multiparous, nonlactating, presynchronized Nelore cows received a progesterone-releasing device and estradiol benzoate on Day–10 (D−10). Animals received cloprostenol (large follicle-large CL group; LF-LCL; N = 35) or not (small follicle-small CL group; SF-SCL; N = 39) on D−10. Progesterone devices were withdrawn and cloprostenol administered 42 to 54 hours (LF-LCL) or 30 to 36 hours (SF-SCL) before GnRH treatment (D0). Tissues were collected at slaughter on D7. Transcriptional profiling of the endometrial tissue was performed by RNA-seq and protein markers for proliferation and apoptosis were identified by immunohistochemistry. Results: Functional enrichment data indicated that LF-LCL endometrium expressed greater abundance of genes associated with biosynthetic and metabolic processes, whereas SF-SCL endometrium .gene expression profile was biased towards cell proliferation. Extracellular matrix-related genes were also upregulated in the SF-SCL endometrium suggesting reorganization of the ECM towards a proliferation permissive phenotype. Immunohistochemistry data confirmed the greater proliferative activity observed in SF-SCL endometrium I comparison to LF-LCL counterparts, and indicated a time-related transition within experimental group. In conclusion, the periovulatory endocrine milieu regulates bovine endometrial gene expression. Furthermore, timing and amplitude of ovarian steroid secretion pattern seem to determine the transition from a proliferation permissive to a biosynthetic and metabolically active endometrial phenotype, which may be associated with the preparation of an optimally receptive uterine environment. Conclusion: the periovulatory endocrine milieu affected D7 endometrial molecular signature. Main pathways affected were related to cell proliferation, ECM composition and remodeling, biosynthetic and metabolic processes. Reported data further suggest that the endometrial tissue from LF-LCL cows experienced an early proliferative phase (D4), whereas the SF-SCL endometrium, exposed to a distinct periovulatory endocrine environment, expressed a delayed onset of the proliferative activity (D7).

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Endometrium of hormone-treated postmenopausal women

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