Association between Daily Dietary Calcium Intake and the Risk of Cardiovascular Disease (CVD) in Postmenopausal Korean Women.

We aimed to evaluate the association between daily dietary calcium intake and the risk of cardiovascular disease (CVD) in postmenopausal women using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included 12,348 women aged 45-70 years who had reached natural menopause. They were classified into three groups according to daily dietary calcium intake: <400 mg, 400-800 mg, and >800 mg. The risks of CVD, stroke, angina, and myocardial infarction were assessed in each group. Further, we performed subgroup analysis according to the post-menopause duration (≤10 vs. >10 postmenopausal years). We performed logistic regression analysis with adjustment for age, menopausal age, income, urban area, education, insulin use, body mass index, hypertension, diabetes mellitus, dyslipidemia, high alcohol intake, smoking, exercise, oral contraceptive use, and hormonal therapy use. Calcium intake level was not significantly associated with the risk of CVD in the total population and the ≤10 postmenopausal years subgroup. However, in the >10 postmenopausal years subgroup, daily calcium intake >800 mg was associated with significantly decreased risks of all CVD (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11-0.64), stroke (OR, 0.06; 95% CI, 0.01-0.42), and myocardial infarction (OR, 0.27; 95% CI, 0.11-0.64). Our findings suggest that a dietary calcium intake of >800 mg/day decreases the risk of CVD events in women who have been menopausal for >10 years.

Hormone replacement therapy and breast cancer incidence in Korean women.

OBJECTIVES: After the 2002 Women's Health Initiative (WHI) study, the global use of menopausal hormone therapy (MHT) declined, and despite subsequent studies indicating a low risk of breast cancer, concerns about MHT usage persist. We examined the relationship between changes in MHT use and changes in the incidence of breast cancer from 2002 to 2020 in South Korea. STUDY DESIGN: This study used tumor registry information from 2002 to 2020 from the Korean Statistical Information Service and analyzed the incidence rate of invasive breast cancer in women, who were divided into two age groups: <50 and >50 years. The numbers of MHT prescriptions in Korea between 2002 and 2020 was determined from pharmacy data. RESULTS: The incidence of breast cancer per 100,000 women in South Korea increased from 34.3 in 2002 to 96.4 in 2020. Breast cancer incidence rates increased annually in both groups of women (those aged under and over 50 years), with no significant difference between the two (p = 0.614). Prescriptions for estrogen therapy (ET) in 2020 were 52.7 % lower than those in 2002. Prescriptions for estrogen-progesterone therapy (EPT) decreased by 27.9 % over the same period. Conversely, tibolone prescriptions, which had initially decreased by 25.4 % in 2004, subsequently showed a steady increase and were 93.6 % higher in 2020 than in 2002. CONCLUSION: The incidence of breast cancer increased annually in Korean women of all ages; however, the use of ET and EPT for MHT has declined since 2002, particularly the use of EPT after 2010. MHT, especially EPT, did not significantly increase the incidence of breast cancer in Korean women.

Relationship between menopausal hormone therapy and incidence of fractures in postmenopausal women.

OBJECTIVE: Long-term protective effects of menopausal hormone therapy (MHT) at fractures with different doses and components are controversial. We analyzed the effect of MHT on the incidence of spine and femur fractures according to MHT type, age at commencement, duration and dose of hormones in Korean women. METHOD: This retrospective study evaluated propensity score-matched patients with MHT from the Korean National Health Insurance Service database. Among women aged ≥50 years with menopause between 2004 and 2007, spine and femur fracture incidence until 2017 was analyzed in 36,446 women who had received MHT for >1 year. Estrogen-progesterone therapy (EPT), estrogen-only therapy (ET) or tibolone therapy was conducted. RESULTS: EPT significantly lowered the incidence of spine and femur fractures with a conventional dose, but not with a low dose. Tibolone significantly decreased the incidence of spine fractures in women aged 50-59 years when used for >5 years, and the incidence of femur fractures in women older than 60 years when used for >3 years. ET significantly lowered the risk of femur fractures when estradiol was used for >5 years. CONCLUSION: In menopausal women, all MHT including conventional-dose EPT, ET and tibolone tended to lower the incidence of fractures. The effects, however, varied with the type of fracture and type of MHT.

Effect of catheter-directed ethanol sclerotherapy on ovarian reserve in patients with recurrent endometrioma: comparative analysis with primary endometriosis.

OBJECTIVE: Catheter-directed ethanol sclerotherapy (CDS) is known to less affect the ovarian function, with comparable efficacy. This study aims to investigate the change in ovarian reserve after catheter-directed ethanol sclerotherapy in patients with recurrent endometrioma, as compared to primary endometrioma. MATERIALS AND METHODS: Retrospective, observational study. Electronic medical records and images of patients with endometrioma who underwent CDS from August 2014 to April 2022 at a single institution were obtained. Patients aged > 18 years old and with anti-Müllerian hormone (AMH) level between 0.8 and 10.0 with regular menstruation were enrolled. Cyst diameter, laterality, AMH level, and CA-125 level before and after 1 month, 6 months, 1 year, 2 years, and 3 years of sclerotherapy were obtained. RESULTS: A total of 180 patients were fit for analysis. There was no statistical difference in age and cyst size between the two groups. Mean values of AMH in each group were 3.35 in the primary group and 3.00 in the recurrent group prior to the procedure (p = 0.347). There was no significant difference in delta value of AMH after sclerotherapy in both groups at each follow-up period. Also, this result was consistent when stratified by laterality, preprocedural AMH level, and initial size of endometrioma. No case of recurrence was reported in both groups. CONCLUSIONS: The effect of CDS on ovarian reserve is not inferior in recurrent endometrioma compared to primary endometrioma. Since sclerotherapy is known to less deteriorate the ovarian function than surgical removal of endometrioma, clinician could consider this as the first-line therapy in patients with recurrent endometrioma. CLINICAL RELEVANCE STATEMENT: Catheter-directed ethanol sclerotherapy for patients with recurrent endometrioma has similar effect on ovarian reserve compared to patients with primary endometrioma. KEY POINTS: • Secondary surgery for endometrioma has significant deleterious effect on ovarian function. • Catheter-directed sclerotherapy (CDS) for endometrioma had equally minimal adverse effect on ovarian reserve, represented as anti-Müllerian hormone (AMH), in both primary and recurrent groups. • Physicians should consider CDS for patients with recurrent endometrioma who desire to preserve ovarian function.

Tibolone and Breast Cancer.

Tibolone, a selective tissue estrogenic activity regulator, is a synthetic steroid with distinct pharmacological and clinical characteristics in contrast to conventional menopausal hormone therapy. Tibolone induces estrogenic activity in the brain, vagina, and bone but remains inactive in the endometrium and breast. In particular, several studies have investigated whether tibolone usage increases the risk of breast cancer. This study aims to determine the effects of tibolone on the breast by focusing on the relation between tibolone use and breast cancer. Our investigation emphasizes recent studies, particularly those based on Asian populations.

BRAK and APRIL as novel biomarkers for ovarian tumors.

Aims: To evaluate BRAK and APRIL in serum samples from healthy patients and an ovarian tumor group and analyze their effective value as biomarkers. Materials & methods: BRAK and APRIL were measured in 197 serum samples including 34 healthy controls, 48 patients with benign ovarian cysts and 115 patients with ovarian cancer, and the best statistical cut-off values were calculated. Then, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value for selected cut-off points were assessed. Results: The healthy control group had statistically significant higher BRAK and lower APRIL than the ovarian tumor group. BRAK was excellent for differentiating healthy patients from patients with ovarian tumors, showing area under the receiver operating characteristic curve 0.983, 98.16% sensitivity and 100% specificity. When BRAK was combined with APRIL and CA-125, it also played a role in distinguishing benign cysts from malignancies with area under the curve 0.864, 81.74% sensitivity and 79.17% specificity. Conclusions: BRAK and APRIL are good candidates for ovarian tumor biomarkers.

MicroRNA-139-5p Regulates Fibrotic Potentials via Modulation of Collagen Type 1 and Phosphorylated p38 MAPK in Uterine Leiomyoma.

PURPOSE: This study aimed to elucidate whether microRNA-139-5p is involved in the pathogenesis of uterine leiomyoma. MATERIALS AND METHODS: Human leiomyoma and matched human smooth muscle samples were obtained from 10 women who underwent hysterectomy for uterine leiomyoma. MicroRNA (miRNA) expression was analyzed by quantitative real-time polymerase chain reaction. To assess the effects of miR-139-5p on cultured leiomyoma cells, cell migration, collagen gel contraction, wound healing, and the expression levels of hallmark proteins were evaluated in cells transfected with a miR-139-5p mimic. RESULTS: The expression of miR-139-5p was significantly lower in leiomyoma tissues than in matched smooth muscle tissues. Restored miR-139-5p expression in miR-139-5p mimic-transfected human leiomyoma cells resulted in decreased contractility of the ECM and cell migration. In addition, upregulation of miR-139-5p decreased the protein expression of collagen type 1 and phosphorylated p38 MAPK. CONCLUSION: Expression of miR-139-5p is downregulated in leiomyoma cells and modulation of miR-139-5p may be involved inthe pathogenesis of leiomyomas through the regulation of collagen type 1 and phosphorylated p38 MAPK. Therefore, miR-139-5p is a potential therapeutic target for leiomyoma.

Hormone autocrination by vascularized hydrogel delivery of ovary spheroids to rescue ovarian dysfunctions.

The regeneration potential of implantable organ model hydrogels is applied to treat a loss of ovarian endocrine function in women experiencing menopause and/or cancer therapy. A rat ovariectomy model is used to harvest autologous ovary cells while subsequently producing a layer-by-layer form of follicle spheroids. Implantation of a microchannel network hydrogel with cell spheroids [vascularized hydrogel with ovarian spheroids (VHOS)] into an ischemic hindlimb of ovariectomized rats significantly aids the recovery of endocrine function with hormone release, leading to full endometrium regeneration. The VHOS implantation effectively suppresses the side effects observed with synthetic hormone treatment (i.e., tissue overgrowth, hyperplasia, cancer progression, deep vein thrombosis) to the normal levels, while effectively preventing the representative aftereffects of menopause (i.e., gaining fatty weight, inducing osteoporosis). These results highlight the unprecedented therapeutic potential of an implantable VHOS against menopause and suggest that it may be used as an alternative approach to standard hormone therapy.

Aberrant Expression of Sodium-Potassium-Chloride Cotransporter in Endometriosis.

Cell membrane ion channels have important roles in cell migration during cancer development and metastasis. Although endometriosis is a benign gynecological disease, some migration and invasion characteristics of endometriosis are similar to those of cancer. However, only a few studies have examined cell membrane ion channels and their associations with endometriosis. This study aimed to investigate the effects of these ion channels on development of endometriosis. A total of 39 women who underwent laparoscopic ovarian cyst enucleation were included in the study population. Eutopic endometrium or ectopic endometrium tissues were obtained from each patient based on allocation to an endometriosis group (n=21) or a control group (n=18). Quantitative real-time PCR (qRT-PCR) and western blot analyses were performed to quantify NKCC1, NKCC2, and CLCN3 mRNA expression and protein concentrations. SiRNA transfection and migration assays of the endometrial stromal cells were performed to test the effects of the ion channels on the migration ability. The qRT-PCR and western blot analyses revealed significantly elevated mRNA expression and protein expression of NKCC1, NKCC2, and CLCN3 in the ectopic endometrial tissue from the patients with endometriosis (p < 0.05). Migration assay of siRNA transfected cells suggested a decreased migratory potential of the endometrial stromal cells (p < 0.001). The magnitudes of expression of NKCC1, NKCC2, and CLCN3 were positively correlated with endometrioma size. The increased expression of NKCC1, NKCC2, and CLCN3 in endometriosis offers opportunities to understand mechanisms of endometriosis and develop novel therapeutic approaches.

Identification of Serum Biomarkers for Diagnosis of Endometriosis Using Multiplex Immunoassays.

Endometriosis is a common gynecologic disorder characterized by chronic pelvic pain, dysmenorrhea, and infertility. Although this condition places significant financial burden on the healthcare system and negatively affects patient's quality of life, the pathophysiology of the disease remains unclear, and noninvasive diagnostic methods are insufficient. The object of this study was to identify potential biomarkers for endometriosis from peripheral blood. We hypothesized that serum biomarkers modified in endometriosis patients would be detected by multiplex cytokine panel, and identification of a combination of these biomarkers would improve diagnostic power. A total of 141 women, aged 15-52 years with regular menstruation, participated in this study. Twenty-one serum cytokines were detected using the commercially available MILLIPLEX MAP Human Cytokine/Chemokine Kit Panel IV. Among these cytokines, breast- and kidney-expressed chemokine (BRAK)/chemokine (C-X-C motif) ligand 14 (CXCL14) was significantly decreased, and proliferation-inducing ligand (APRIL)/tumor necrosis factor ligand superfamily member 13 (TNFSF13) was significantly increased in endometriosis group. APRIL/TNFSF13 and BRAK/CXCL14 alone or in combination, however, failed to show adequate sensitivity or specificity for the diagnosis of endometriosis. Combination of APRIL/TNFSF13 and BRAK/CXCL14 with serum CA-125 levels yielded significantly higher sensitivity (71.2%) for detecting endometriosis without compromising specificity (80.8%) than CA-125 alone in a logistic regression model (P = 0.050). In conclusion, we identified a biomarker combination that detects endometriosis better than CA125 alone. Therefore, we conclude that multiplex cytokine panel is an efficient method for detecting endometriosis, and analysis of additional cytokine panels may lead to identification of a novel biomarker combination with superior diagnostic power.

MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27Kip1 Pathway In Vitro.

Uterine leiomyoma is found in ~50-80% of women of a reproductive age and is the most common reason for hysterectomy. Recently, posttranscriptional gene silencing by microRNAs (miRs) has been reported as a mechanism for regulating gene expression stability in the pathogenesis of uterine leiomyomas. In this study, miR microarray analysis of leiomyomas and paired myometrial tissue revealed numerous aberrantly expressed miRs, including miR-150. In functional assays, transfection with miR-150 mimic resulted in decreased migration and fibrosis, implying an inhibition of leiomyoma growth. To identify the target genes of miR-150 in leiomyoma, gene set analysis and network analysis were performed. To overcome the limitations of in silico analysis, changes in expression levels of hallmark genes in leiomyoma after transfection with a miR-150 mimic were also evaluated using qRT-PCR. As a result, the Akt/p27Kip1 pathway was presumed to be one of the target pathways of miR-150. After transfecting cultured leiomyoma cells with the miR-150 mimic, expression levels of its target gene Akt decreased, whereas those of p27Kip1 increased significantly. Our results suggest that miR-150 affects the cell cycle regulation in uterine leiomyoma through the Akt/p27Kip1 pathway.