Expression levels of genes encoding phase I and phase II estrogen-metabolizing enzymes:
CYP1A1,
CYP1A2,
CYP1B1,
CYP3A5,
CYP3A7,
SULT1A1,
SULT1E1,
SULT2B1,
COMT,
UGT2B7, and
GSTP1 were studied by ...real-time PCR in 38 samples of cancerous and adjacent control endometrium. We found significantly lower levels of
CYP1B1 and
CYP3A7, higher levels of
SULT2B1,
UGT2B7 and
GSTP1, and no differences in expression of
COMT,
CYP1A1,
CYP3A5,
SULT1E1 and
SULT2A1 in the endometrial cancers. The CYP1B1 and COMT proteins were also examined by Western blotting and immunohistochemical staining, supporting the real-time PCR analysis. Lower levels of CYP1B1 detected in cancerous endometrium suggest its important role in control, precancerous tissue. Additionally, we showed for the first time higher protein levels of soluble COMT in cancerous endometrium, and higher levels of membrane-bound COMT in control, precancerous endometrium. The importance of the changed ratio between soluble and membrane-bound COMT still needs to be evaluated in further studies.
► AKR1B1 and AKR1B10 are implicated in the development of various cancers. ► AKR1B1 expression is decreased in cancerous endometrium of post-menopausal women. ► Higher mRNA and lower protein levels ...of AKR1B10 are seen in cancerous endometrium. ► In endometrium, AKR1B1 and AKR1B10 appear involved in initiation of carcinogenesis.
Endometrial cancer is associated with enhanced cell proliferation due to high concentrations of estrogens, and decreased cell differentiation due to low levels of progesterone and retinoic acid. It is also associated with aberrant inflammatory responses and concomitant increased production of prostaglandins. The human members of the aldo–keto reductase 1B (AKR1B) subfamily, AKR1B1 and AKR1B10, have roles in these processes and can thus be implicated in endometrial cancer. To date, there have been no reports on the expression of AKR1B1 in endometrial cancer, while AKR1B10 has only been studied at the cellular level. To evaluate the roles of these AKR1B enzymes, we investigated expression of AKR1B1 and AKR1B10 in 47 paired samples of cancerous and adjacent control endometrium at the mRNA and protein levels, by quantitative PCR, Western blotting and immunohistochemistry staining. There were significantly lower mRNA and protein levels of AKR1B1 in cancerous tissues compared to adjacent endometrium. The gene expression of AKR1B10 at the mRNA level was significantly increased, while there were significantly decreased protein levels. Immunohistochemistry revealed that both of these enzymes were present in all of the samples, and are located in epithelial cells of cancerous and control endometrial glands. Elevated levels in adjacent non-cancerous tissues imply that these enzymes are more important in the initiation of endometrial cancer than in its progression. To the best of our knowledge, this is the first report on the expression of AKR1B1 and AKR1B10 in endometrial cancer. Further studies are needed to define the precise roles of these enzymes in the pathogenesis of endometrial cancer.
Endometrial cancer is the most common malignancy of the female genital tract. Its incidence correlates with prolonged estrogen stimulation unopposed by progesterone or synthetic progestins. Estrogen ...and progestin action is regulated at the pre-receptor level, by interconversion of active hormones (estradiol (E2), progesterone (P)) with their inactive counterparts (estrone (E1), 20α-hydroxyprogesterone (20α-OHP)) in target tissues. Expression of enzymes that control the ratio of E2 and P may thus play role in the disease process. We first confirmed that AKR1C1 (human 20α-hydroxysteroid dehydrogenase) in a cellular context inactivates P by forming 20α-OHP but does not catalyze the reverse reaction. We next examined the expression of AKR1C1 and AKR1C3 (type 5 17β-hydroxysteroid dehdyrogenase) in 16 paired specimens of endometrial cancer and adjacent normal endometrium. Quantification by isoform specific real-time PCR revealed higher expression of AKR1C1 in nine specimens and higher expression of AKR1C3 in four specimens of endometrial cancer. Importantly, upregulation of both enzymes in the same specimen was observed. Since AKR1C1 inactivates P its elevated expression in diseased endometrium may contribute to diminished protection by P, while eleveated expression of AKR1C3 which forms E2 in vivo, may contribute to the enhanced estrogen action. It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2
Endometriosis is defined as the presence of endometrial glands and stroma within extrauterine sites, and it is well known that endometriosis is an estrogen-dependent disease. The defective formation ...and metabolism of steroid hormones is responsible for the promotion and development of endometriosis. In the present study we examined the mRNA levels of six enzymes that are involved in the metabolism of estrogen and progesterone - aromatase, 17β-hydroxysteroid dehydrogenase (17β-HSD) types 1, 2 and 7, sulfatase and sulfotransferase - and of the steroid receptors - estrogen receptors α and β (ERα, ERβ) and progesterone receptors A and B (PRAB) - implicated in human ovarian endometriosis. We analyzed 16 samples of ovarian endometriosis and 9 of normal endometrium. The real-time polymerase chain reaction analyses revealed that six of the nine genes investigated are differentially regulated. Aromatase, 17β-HSD types 1 and 7, sulfatase and ERβ were statistically significantly upregulated, while ERα was significantly downregulated, in the endometriosis group compared with the control group. There were no significant differences in 17β-HSD type 2, sulfotransferase and PRAB gene expression. Our results indicate that, in addition to the previously reported upregulation of aromatase, upregulation of 17β-HSD types 1 and 7 and sulfatase can also increase the local estradiol concentration. This could thus be responsible for the estrogen-dependent growth of endometriotic tissue. Surprisingly ERα was downregulated.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Deep infiltrating endometriosis with colorectal involvement is a complex disorder, often requiring segmental bowel resection. Complete removal of all visible lesions is considered the adequate ...treatment of infiltrating endometriosis in order to reduce recurrence. In this article, we describe our experience with laparoscopic management of deep infiltrating endometriosis with involvement of the rectum.
A retrospective analysis of data from patients with deep infiltrating endometriosis with rectal involvement who underwent a laparoscopic surgery in the years 2002-2009 at the Department of Obstetrics and Gynecology at our institution was done.
Between 2002 and 2009, a laparoscopic partial rectal resection was performed in 52 patients, and laparoscopic disk resection was performed in 4 cases with deep infiltrating endometriosis. The mean age of patients was 34.4 years (range, 22-62 years). Preoperative symptoms included dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. The laparoscopic procedure was converted to formal laparotomy in 3 patients (5.4%). The mean duration of surgery was 145 minutes. Postoperative complications included 3 cases of anastomotic leakage with rectovaginal fistula in two cases and intraabdominal bleeding in 1 case. The mean hospital stay was 7 days. Postoperatively, nine patients had a normal delivery, two of them after in vitro fertilization treatment.
Laparoscopic rectal resection for deep infiltrating endometriosis is a relatively safe procedure, when performed by a surgeon and a gynecologist with sufficient experience in laparoscopic colorectal surgery.
► 78 out of 172 genes differentially expressed in ovarian endometriosis. ► 36 genes associate with terms signal peptide, extracellular region and secreted. ► 23 new estrogen-related genes associate ...with endometriosis. ► Differential expression of
ESR1,
ESR2,
PGR,
BGN confirmed by immunohistochemistry.
In the search for novel biomarkers of endometriosis, we selected 152 genes from the GeneLogic database based on results of genome-wide expression analysis of ovarian endometriosis, plus 20 genes related to estrogen metabolism and action. We then performed low-density array analysis of these 172 genes on 11 ovarian endometriosis samples and 9 control endometrium samples. Principal component analysis of the gene expression levels showed clear separation between the endometriosis and control groups. We identified 78 genes as differentially expressed. Based on Ingenuity pathway analysis, these differentially expressed genes were arranged into groups according to biological function. These analyses revealed that 32 differentially expressed genes are estrogen related, 23 of which have not been reported previously in connection with endometriosis. Functional annotation showed that 25 and 22 genes are associated with the biological terms “secreted” and “extracellular region”, respectively. Differential expression of 4 out of 5 genes related to estrogen metabolism and action (
ESR1,
ESR2,
PGR and
BGN) was also confirmed by immunohistochemistry. Our study thus reveals differential expression of several genes that have not previously been associated with endometriosis and that encode potential novel biomarkers and drug targets.
Estrogen-dependent endometrial cancer is related to unopposed and prolonged estrogen stimulation. We examined the expression of estrogen-metabolizing enzymes in correlation with the ERα and ERβ ...estrogen receptors in human endometrial Ishikawa adenocarcinoma cells and in endometrial cancer specimens and adjacent normal endometrium from the same patients. Real-time PCR analysis revealed that both estrogen receptors and selected estrogen-metabolizing enzymes were expressed in the Ishikawa cells and in endometrial tissue. We detected higher expression of ERα than ERβ, higher expression of sulfatase than sulfotransferase and low expression of aromatase in the Ishikawa cells and the tissue, as well as higher levels of type 2 17β-hydroxysteroid dehydrogenase (17β-HSD) in normal and diseased tissue than in the Ishikawa cells. When we compared the expression in endometrial cancer samples and in the adjacent normal endometrium, ERα and ERβ, sulfatase and sulfotransferase were seen to be downregulated in the majority of the cancerous tissue specimens.
Abstract In the management of obstructive azoospermia (OA), microsurgery is often replaced by testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). Testicular biopsy and ...microsurgical side-to-side epididymovasostomy were performed in 34 azoospermic men with OA mostly due to inflammation. Ductal system patency was recovered in 21 (63.6%) men and natural pregnancy achieved in 13 (38.2%) of couples. Using multiple logistic regression analysis, it was found that ductal system patency and pregnancy were influenced by male and female age and testicular histology. The chance of obtaining patency was three times higher when male age was <38 years and two times higher when normal spermatogenesis alone was found to be present compared with mixed lesions. The chance of achieving a pregnancy was three times higher when the female partner’s age was <29 years or normal spermatogenesis alone was present. The pregnancy rates obtained after surgery were not statistically different from those obtained by TESE-ICSI, but when also considering multiple pregnancies, miscarriages and side effects, the results obtained with surgery are better than those obtained with TESE-ICSI.
Abstract Factors that influenced the clinical results of 220 first-attempt intracytoplasmic sperm injection (ICSI) cycles with testicular spermatozoa were evaluated in 107 men with non-obstructive ...azoospermia, 72 with obstructive azoospermia and 41 with aspermia. Linear and logistic regression analysis showed that the fertilization rate depended positively on Johnsen score ( P = 0.016) and on the type of ovarian stimulation: a higher fertilization rate was observed after ovarian stimulation with agonist and recombinant FSH than after stimulation with agonist and urinary menopausal gonadotrophin ( P = 0.026). Embryo development to the blastocyst stage was predicted positively by the number of injected oocytes ( P = 0.016) and negatively by male FSH concentration ( P = 0.019). A higher proportion of blastocysts developed after the use of frozen–thawed spermatozoa in comparison to fresh spermatozoa ( P = 0.034). Embryo development to the blastocyst stage influenced pregnancy ( P = 0.002) and live birth outcomes ( P = 0.005); live birth was also predicted by female age ( P = 0.046). Embryo culture to day 5 in comparison to day 2 did not provide higher live birth rates. In azoospermia/aspermia, the ICSI outcome depends on both male factors (FSH, Johnsen score, sperm status and motility) and female factors (age, number of injected oocytes).
Peri-intraventricular hemorrhage (P/IVH) is a common neonatal morbidity among premature infants. The aim of the study was to examine the association between placental and/or fetal inflammation and ...the onset of P/IVH in premature infants.
A prospective study included 125 infants with gestational age 23-29 weeks. Placentas were examined for the presence of chorioamnionitis and funisitis, cord blood was sampled for the measurement of cytokines (IL-6 and IL-8). Fetal inflammation was defined as levels of IL-6 higher than 7.6 pg/ml. P/IVH was defined as early if diagnosed within the 1st day after birth; thereafter P/IVH was defined as late.
Adjusted for the influence of gestational age, early-onset sepsis (OR 3.2, p = 0.045) and no or incomplete antenatal steroid course (OR 6.0, p = 0.001) significantly predicted early P/IVH. Funisitis (OR 1.6, p = 0.06) and fetal inflammation (OR 2.6, p = 0.06) were only partially associated with early hemorrhage. Contrary to that, respiratory distress syndrome (OR 3.4, p = 0.04), mechanical ventilation (OR 5.9, p = 0.008), low blood pressure (OR 3.5, p = 0.02), and vasopressors (OR 5.7, p = 0.002) were associated with late P/IVH. In multivariate analysis no or incomplete steroid course remained independent predictors for early and use of vasopressors for late P/IVH. The interaction of fetal inflammation and vaginal delivery with no or incomplete steroid course increased the risk of early P/IVH.
These results indicate different risk factors for early and late P/IVH. Neither funisitis nor fetal inflammation independently predicts the onset of P/IVH. However, the interaction of fetal inflammation and vaginal delivery with no or incomplete antenatal steroid course increase the risk of early but not also late P/IVH.
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