Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis

Background: Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves.Materials and methods: A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group (n = 38) vs. controls (n = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after H2O2 treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well.Results: Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After H2O2 treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of BRCA1 and Rad51 mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of BRCA1 and BRCA2 mRNA. Serum AMH concentration showed a significant correlation with ovarian BRCA1 mRNA expression in women with endometriosis (p = 0.03).Conclusions: In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian BRCA1 expression correlates wit

Age at First Delivery and Osteoporosis Risk in Korean Postmenopausal Women: The 2008-2011 Korea National Health and Nutrition Examination Survey (KNHANES).

It has been reported in several studies that there may be a significant correlation between reproductive history and the risk of osteoporosis due to the effect of estrogen. Under this hypothesis, however, it is unclear whether the age at first delivery has any major influences on the risk of osteoporosis. Therefore, this study aimed to investigate the relationship between the age at first delivery and the risk of osteoporosis in Korean menopausal women. This study was performed using data from the 2008-2011 Korea National Health and Nutrition Examination Survey and included 2,530 Korean postmenopausal women. The diagnosis of osteoporosis was made using the World Health Organization T-score criteria (T-score ≤ -2.5, at the femoral neck or lumbar spine). Participants were categorized into 3 groups according to age at first delivery: ≤ 23, 24-29, and ≥ 30 years. Older age, lower body mass index, lower calcium intake, later menarche, and earlier menopause increased the risk of osteoporosis, whereas hormone therapy and oral contraceptive use were associated with a decreased risk of osteoporosis. Postmenopausal women whose first delivery occurred at age 24-29 years were shown to have a significantly increased risk of osteoporosis (odds ratio, 2.124; 95% confidence interval, 1.096-4.113; P = 0.026) compared to those who first gave birth after the age of 30 years. These findings suggest that postmenopausal women whose first delivery occurred in their mid to late 20s, a period during which bone mass slowly accumulates to the peak, are at an increased risk of osteoporosis

Association between levels of serum ferritin and bone mineral density in Korean premenopausal and postmenopausal women: KNHANES 2008-2010.

As women go through menopause, serum estrogen decreases and ferritin increases. Decreased serum estrogen is well known to cause detrimental effects on bone health; however, data on the associations of serum ferritin with BMD before and after menopause are still lacking. Therefore, this study aimed to investigate the association between serum ferritin levels and BMD in premenopausal and postmenopausal Korean women.This study was performed using data from the 2008-2010 Korean National Health and Nutrition Examination Survey, including 7300 women (4229 premenopausal and 3071 postmenopausal). BMD was measured using dual X-ray absorptiometry at the femur and the lumbar spine, and serum ferritin levels were measured by chemiluminescent immunoassay.Median serum ferritin levels in postmenopausal women were higher than those in premenopausal women despite the same age ranges. Serum ferritin levels were only significantly correlated with BMD on the lumbar spine (β = -0.189, p-value = 0.005) in premenopausal women after adjusting confounding factors. Additionally, BMD on the lumbar spine had tended to decrease as serum ferritin quartiles increase (P for trend = 0.035) in premenopausal women after adjusting confounding factors. On the other hand, there were no significant associations between serum ferritin levels and BMD on the total femur and, femur neck in premenopausal women, and BMD on the total femur, femur neck, and lumbar spine in postmenopausal women.Increased serum ferritin levels were significantly associated with BMD in premenopausal women, particularly on the lumbar spine, but not in postmenopausal women

Changes in the Expression of TBP-2 in Response to Histone Deacetylase Inhibitor Treatment in Human Endometrial Cells

Histone deacetylase inhibitors (HDACi) induce apoptosis preferentially in cancer cells by caspase pathway activation and reactive oxygen species (ROS) accumulation. Suberoylanilide hydroxamic acid (SAHA), a HDACi, increases apoptosis via altering intracellular oxidative stress through thioredoxin (TRX) and TRX binding protein-2 (TBP-2). Because ROS accumulation, as well as the redox status determined by TBP-2 and TRX, are suggested as possible mechanisms for endometriosis, we queried whether SAHA induces apoptosis of human endometrial cells via the TRX–TBP-2 system in endometriosis. Eutopic endometrium from participants without endometriosis, and ectopic endometrium from patients with endometriosis, was obtained surgically. Human endometrial stromal cells (HESCs) and Ishikawa cells were treated with SAHA and cell proliferation was assessed using the CCK-8 assay. Real-time PCR and Western blotting were used to quantify TRX and TBP-2 mRNA and protein expression. After inducing oxidative stress, SAHA was applied. Short-interfering TRX (SiTRX) transfection was performed to see the changes after TRX inhibition. The mRNA and protein expression of TBP-2 was increased with SAHA concentrations in HESCs significantly. The mRNA TBP-2 expression was decreased after oxidative stress, upregulated by adding 2.5 μM of SAHA. The TRX/TBP-2 ratio decreased, apoptosis increased significantly, and SiTRX transfection decreased with SAHA. In conclusion, SAHA induces apoptosis by modulating the TRX/TBP-2 system, suggesting its potential as a therapeutic agent for endometriosis

Changes in the Expression of TBP-2 in Response to Histone Deacetylase Inhibitor Treatment in Human Endometrial Cells

Histone deacetylase inhibitors (HDACi) induce apoptosis preferentially in cancer cells by caspase pathway activation and reactive oxygen species (ROS) accumulation. Suberoylanilide hydroxamic acid (SAHA), a HDACi, increases apoptosis via altering intracellular oxidative stress through thioredoxin (TRX) and TRX binding protein-2 (TBP-2). Because ROS accumulation, as well as the redox status determined by TBP-2 and TRX, are suggested as possible mechanisms for endometriosis, we queried whether SAHA induces apoptosis of human endometrial cells via the TRX–TBP-2 system in endometriosis. Eutopic endometrium from participants without endometriosis, and ectopic endometrium from patients with endometriosis, was obtained surgically. Human endometrial stromal cells (HESCs) and Ishikawa cells were treated with SAHA and cell proliferation was assessed using the CCK-8 assay. Real-time PCR and Western blotting were used to quantify TRX and TBP-2 mRNA and protein expression. After inducing oxidative stress, SAHA was applied. Short-interfering TRX (SiTRX) transfection was performed to see the changes after TRX inhibition. The mRNA and protein expression of TBP-2 was increased with SAHA concentrations in HESCs significantly. The mRNA TBP-2 expression was decreased after oxidative stress, upregulated by adding 2.5 μM of SAHA. The TRX/TBP-2 ratio decreased, apoptosis increased significantly, and SiTRX transfection decreased with SAHA. In conclusion, SAHA induces apoptosis by modulating the TRX/TBP-2 system, suggesting its potential as a therapeutic agent for endometriosis

Correction: Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.

[This corrects the article DOI: 10.1371/journal.pone.0148165.]

Flow chart of participant enrollment.

<p>Flow chart of participant enrollment.</p