Etiology and Secular Trends in Primary Amenorrhea in 856 Patients: A 17-Year Retrospective Multicenter Study in Korea

Background: This study was performed to evaluate etiologies and secular trends in primary amenorrhea in South Korea. Methods: This retrospective multi-center study analyzed 856 women who were diagnosed with primary amenorrhea between 2000 and 2016. Clinical characteristics were compared according to categories of amenorrhea (hypergonadotropic/hypogonadotropic hypogonadism, eugonadism, disorders of sex development) or specific causes of primary amenorrhea. In addition, we assessed secular trends of etiology and developmental status based on the year of diagnosis. Results: The most frequent etiology was eugonadism (39.8%). Among specific causes, Müllerian agenesis was most common (26.2%), followed by gonadal dysgenesis (22.4%). Women with hypergonadotropic hypogonadism were more likely to have lower height and weight, compared to other categories. In addition, the proportion of cases with iatrogenic or unknown causes increased significantly in hypergonadotropic hypogonadism category, but overall, no significant secular trends were detected according to etiology. The proportion of anovulation including polycystic ovarian syndrome increased with time, but the change did not reach statistical significance. Conclusion: The results of this study provide useful clinical insight on the etiology and secular trends of primary amenorrhea. Further large-scale, prospective studies are necessary.ope

The 2020 Menopausal Hormone Therapy Guidelines

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Management of Endometriosis-Associated Infertility

Endometriosis is a common, chronic disease. Patients typically present with pelvic pain, infertility, and/or an adnexal mass. Results from the limited number of studies that have been published indicate that the true prevalence of endometriosis, along with the associated infertility, has been increasing. Debates about infertility management arise from the contradiction between the contraceptive nature of medical treatments for endometriosis and the unpredictable ovarian reserve after surgery. There is moderate quality evidence that surgery increases clinical pregnancy rate and live birth in minimal to mild endometriosis. However, insufficient evidences which supports the effect of surgery in moderate to severe endometriosis in term of subfertility. On this basis, artificial reproductive technologies have been become the most efficient way of overcoming endometriosisassociated infertility, particularly in stage III/IV endometriosis. The objective of this paper is to review recent trends in endometriosis, from the pathophysiology of the disease to the management of infertility.ope

Serum Thyroid Stimulating Hormone Levels Are Associated with the Presence of Coronary Atherosclerosis in Healthy Postmenopausal Women

Objectives : Menopause is a natural aging process causing estrogen deficiency, accelerating atherogenic processes including dyslipidemia. Prevalence of thyroid dysfunction is also high in postmenopausal women, and it is known to elevate the risk of cardiovascular disease (CVD). Therefore, we are to study on the associations in between serum thyroid stimulating hormone (TSH) and prevalence of CVD in postmenopausal women who have normal thyroid function. Methods : We performed a retrospective review of 247 Korean postmenopausal women who visited the health promotion center from January, 2007 to December, 2009. Postmenopausal women with normal serum TSH were included in the study. Coronary atherosclerosis was assessed by 64-row multidetector computed tomography. Results : In multiple linear regression analysis, serum TSH was associated with serum triglyceride (TG) (β = 0.146, P = 0.023). In multiple logistic regression analysis, increasing age and serum TSH were associated with an increased risk of coronary atherosclerosis in euthyroid postmenopausal women (odds ratio [OR] = 1.107 [1.024-1.197], P = 0.011 and OR = 1.303 [1.024-1.658], P = 0.031, respectively). Conclusions : It revealed that significant predictor of serum TSH was serum TG, and increasing age and TSH were found to have associations with an increased risk of coronary atherosclerosis in euthyroid postmenopausal women. Screening and assessing risks for CVD in healthy postmenopausal women would be helpful before atherosclerosis develops.ope

Decreased bone mineral density is associated with coronary atherosclerosis in healthy postmenopausal women

OBJECTIVE: This study aimed to assess the association between bone mineral density (BMD) and coronary atherosclerosis in healthy postmenopausal women. METHODS: We performed a retrospective review of 252 postmenopausal women who had visited a health promotion center for a routine checkup. BMD of the lumbar spine (L1-L4) and femoral neck was evaluated using dual-energy X-ray absorptiometry, and coronary atherosclerosis was assessed using 64-row multidetector computed tomography. Participants were divided into normal BMD and osteopenia-osteoporosis groups, according to the T-scores of their lumbar spine or femoral neck. RESULTS: Participants with osteopenia-osteoporosis had a significantly higher proportion of coronary atherosclerosis than did those with normal BMD at the lumbar spine (P=0.003) and femoral neck (P=0.004). Osteopenia-osteoporosis at the lumbar spine (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.12 to 7.27) or femoral neck (OR, 3.35; 95% CI, 1.07 to 10.57) was associated with coronary atherosclerosis, after controlling for age and cardiovascular risk factors. CONCLUSION: Decreased BMD is associated with coronary atherosclerosis in healthy postmenopausal women, independent of age and cardiovascular risk factors. Postmenopausal women with decreased BMD may have a higher risk of developing coronary atherosclerosis.ope

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

Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner. Treatment with a TLR4 antagonist and an NF-κB inhibitor resulted in suppression of rHMGB-1-induced HESC proliferation (P<0.05). Levels of IL-6 were significantly decreased following treatment with an NF-κB inhibitor (P<0.05). Our results support the development of altered, pathological endometrium resulted from oxidative stress in normal endometrium. These findings may provide important insights into the changes in endometrium linking the development and progression of endometriosis.ope

Feasibility of three-dimensional reconstruction and automated measurement of fetal long bones using 5D Long Bone

OBJECTIVE: To evaluate the feasibility of five-dimensional Long Bone (5D LB), a new technique that automatically archives, reconstructs images, and measures lengths of fetal long bones, to assess whether the direction of volume sweep influences fetal long bone measurements in three-dimensional (3D) ultrasound and 5D LB, and to compare measurements of fetal long bone lengths obtained with 5D LB and those obtained with conventional two-dimensional (2D) and manual 3D techniques. METHODS: This prospective study included 39 singleton pregnancies at 26+0 to 32+0 weeks of gestation. Multiple pregnancies, fetuses with multiple congenital anomalies, and mothers with underlying medical diseases were excluded. Fetal long bones of the lower extremities-the femur, tibia, and fibula were measured by 2D and 3D ultrasound, and 5D LB, by an expert and non-expert examiner. First, we analyzed the 3D ultrasound and 5D LB data according to 2 different sweeping angles. We analyzed intra- and inter-observer variability and agreement between ultrasound techniques. Paired t-test, interclass correlation coefficient, and Bland-Altman plot and Passing-Bablok regression were used for statistical analysis. RESULTS: There was no statistical difference between long bone measurements analyzed according to 2 different volume-sweeping angles by 3D ultrasound and 5D LB. Intra- and inter-observer variability were not significantly different among all 3 ultrasound techniques. Comparing 2D ultrasound and 5D LB, the interclass correlation coefficient for femur, tibia, and fibula was 0.91, 0.92, and 0.89, respectively. CONCLUSION: 5D LB is reproducible and comparable with conventional 2D and 3D ultrasound techniques for fetal long bone measurement.ope

Ginsenoside Rg3 Decreases Fibrotic and Invasive Nature of Endometriosis by Modulating miRNA-27b: In Vitro and In Vivo Studies

This research aimed to evaluate the potential therapeutic effects of Rg3 on endometriosis and identify target miRNAs. We designed an in vitro study using human endometrial stromal cells (HESCs) obtained from patients with endometriosis and an in vivo study using mouse models. HESCs were treated with Rg3-enhanced red ginseng extract (Rg3E); real-time PCR and microarray profiling, transfection, and western blot were performed. Mouse endometriosis models were developed and supplemented with Rg3E for 8 weeks. Gross lesion size and fibrotic character were analyzed in the mouse models. RNA levels of Ki-67, col-1, CTGF, fibronectin, TGF-β1, MMP2 and MMP9 significantly decreased in HESCs after Rg3E treatment. Microarray analysis revealed downregulation of miR-27b-3p, which is related to fibrosis modulation. Expression of miR-27b-3p was significantly higher in HESCs from patients with endometriosis than that of controls, and Rg3E treatment significantly decreased its expression; the contraction and migration assay revealed significant reductions in both fibrosis and migration potential in Rg3E-treated HESCs from endometriosis patients. A decrease in size and fibrotic character of endometrial lesions from the Rg3E groups was observed in vivo. In conclusion, Rg3 effectively altered fibrotic properties of HESCs from patients with endometriosis, which is likely associated with miR-27b-3p modulation.ope

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.ope

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.ope