Ovarian steroid dependence of endoplasmic reticulum stress involvement in endometrial cell apoptosis during the human endometrial cycle.

Endoplasmic reticulum (ER) stress is a common cellular stress response that enhances apoptosis to trigger cell death. However, recent studies have shown that estrogen suppresses apoptosis by inhibiting ER stress in some cell types, suggesting that ER stress-induced apoptosis is regulated by ovarian steroid hormones. In endometrial cells, ER stress may also be controlled by ovarian steroid hormones and could be involved in apoptosis induction during the menstrual cycle. To test this hypothesis, we elucidate whether ER stress is regulated by ovarian steroid hormones in human endometrial cells and if it is involved in apoptosis induction. Specifically, we sought to determine the effects of estrogen and progesterone on the PERK/eIF2α/ATF4/CHOP pathway, a pro-apoptotic pathway mediated by ER stress. Our results show that ER stress maker GRP78 expression was increased in human endometrial Ishikawa and endometrial stromal cells (ESCs) treated with tunicamycin. Addition of estrogen decreased tunicamycin-induced GRP78 expression. In contrast, progesterone treatment increased GRP78 in estrogen-treated Ishikawa and ESCs, which significantly increased CHOP expression through phosphorylation of eIF2α and upregulation of ATF4. This upregulation was accompanied by an increased apoptosis induction. The progesterone-induced increase in apoptosis was reversed by either mifepristone (progesterone receptor modulator) or salubrinal (ER stress inhibitor). Furthermore, our in vivo results also showed that GRP78, CHOP expression and apoptosis were significantly increased in endometrial cells during the secretory phase as well as by in vitro treatment with progesterone. In conclusion, our results suggest that estrogen inhibits ER stress in human endometrial cells. This inhibition is reversed by progesterone during the secretory phase, and this is directly involved in apoptosis induction.

Clinical utility of newly developed highly purified human menopausal gonadotrophins: a randomized controlled trial.

The aim of this study was to evaluate the safety and efficacy of IVF-M HP, a newly developed highly purified human menopausal gonadotrophin preparation, for ovarian stimulation in women with infertility undergoing IVF, intracytoplasmic sperm injection (IVF-ICSI) and embryo transfer using a GnRH antagonist protocol. This was a multicentre, randomized, active-controlled, parallel design, open-label, non-inferiority clinical study. Of the 112 patients randomized for treatment using the GnRH antagonist protocol, 111 were treated. No significant difference was found in the number of oocytes retrieved from the IVF-M HP and Menopur groups (13.1 ± 7.6 versus 10.3 ± 6.7, respectively). The lower limit of the one-sided 97.5% confidence interval for the difference between the groups was -0.25, i.e., greater than the pre-defined non-inferiority margin (-5). Therefore, the IVF-M HP treatment was considered non-inferior to Menopur. Furthermore, no significant difference was observed between the groups in the number of good-quality oocytes, leading follicles, good-quality embryos, or in fertilization, implantation, positive beta-HCG and clinical pregnancy rates. The safety analysis revealed that 40.4% and 35.2% in the IVF-M HP and Menopur groups, respectively, reported adverse events. In conclusion, IVF-M HP had comparable clinical efficacy and safety profiles to Menopur.

Disease-specific Growth Charts of Marfan Syndrome Patients in Korea.

Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to λ, µ, and σ, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.

Five-year recurrence pattern of mature cystic teratoma according to operation type in young women.

OBJECTIVE: To find cumulative recurrence rate and risk factors for recurrence in young women with mature cystic teratoma (MCT). METHODS: Patients aged 10-29 years with MCT confirmed by their first ovarian surgery between 2000 and 2018 were included in the study. To rule out residual lesions, only patients with no MCT-suspected lesions on imaging within 1 year after surgery were included in the study. Patients who had not undergone imaging tests from 1 year after surgery or had other findings on biopsy were excluded. RESULTS: The present study included 372 (84.2%) patients with cystectomy and 70 (15.8%) patients with oophorectomy. The 5-year cumulative recurrence rates for each patient group were 11.2% and 20.3%, respectively. The hazard rate of recurrence was higher in the oophorectomy group than the cystectomy group within 5 years after surgery. Large tumor size (hazard ratio [HR] 2.59; 95% confidence interval [CI] 1.11-6.08) and bilaterality (HR 2.65; 95% CI 1.27-5.52) were significant predictors of recurrence in the cystectomy group. CONCLUSION: The 5-year cumulative recurrence rate after surgery in young women with ovarian MCT was 11.2% in the cystectomy group and 20.3% in the oophorectomy group. Risk factors for recurrence after cystectomy were large tumor size and bilaterality.

A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion.

STUDY OBJECTIVE: To estimate the efficacy of alginate carboxymethylcellulose hyaluronic acid (ACH) gel to prevent intrauterine adhesions after hysteroscopic surgery in comparison with carboxymethylcellulose hyaluronic acid (CH) gel, which is known as an effective adhesion inhibitor. DESIGN: Randomized, multicenter, single-blind, clinical trial (Canadian Task Force classification I). SETTING: Tertiary university hospital. PATIENTS: One hundred eighty-seven patients with a surgically treatable intrauterine lesion (myomas, polyps, septa, intrauterine adhesion, dysfunctional uterine bleeding). INTERVENTIONS: Patients were randomized to 2 groups: hysteroscopic surgery plus intrauterine application of ACH or CH. MEASUREMENTS AND RESULTS: The rate of adhesion formation and the adhesion severity score with type and extent were calculated 4 weeks after surgery. The ACH group had results that were comparable to the CH group in terms of the development of intrauterine adhesions at 4 weeks follow-up. The adhesion severities were not different between the 2 groups. In a subgroup without baseline intrauterine adhesion, the ACH group showed a lower intrauterine adhesion rate than the CH group (p = .016). CONCLUSIONS: ACH had a comparable efficacy to CH in terms of the adhesion rate and severity. In the case of no baseline intrauterine adhesion, intrauterine application of ACH after hysteroscopic surgery had a lower rate of intrauterine adhesion than application of CH.

The incidence and characteristics of uterine bleeding during postoperative GnRH agonist treatment combined with tibolone add-back therapy in endometriosis patients of reproductive age.

OBJECTIVES: This study was undertaken to evaluate the incidence and the factors associated with uterine bleeding while taking GnRH agonist treatment combined with tibolone add-back therapy in endometriosis patients of reproductive age. STUDY DESIGN: The medical records of 188 endometriosis (stages III-IV) patients of reproductive age receiving postoperative GnRH agonist treatment combined with tibolone add-back therapy for 6 months were reviewed. Clinical features were analyzed and compared between the two groups: Group A, patients without an episode of uterine bleeding (n=137) and Group B, patients that had experienced uterine bleeding (n=51). RESULTS: Demographic profiles were not different in the two groups. The incidence of uterine bleeding was 27.1% and irregular spotting was the most frequent bleeding pattern. The proportion of patients who received ovarian surgery during pelviscopy was higher in Group B (p<0.05), but other clinical characteristics were not different between two groups. CONCLUSIONS: The incidence of uterine bleeding was 27.1%. And, the proportion of patients who received ovarian surgery was higher in patients with uterine bleeding.

Experience with specially designed pored polyacetal mold dressing method used in McIndoe-style vaginoplasty.

INTRODUCTION: Appropriate postoperative care and prolonged use of the mold are prerequisites for achieving successful results in McIndoe-style vaginoplasty. OBJECTIVE: We introduce a specially designed pored polyacetal mold to maintain the reconstructed vagina, with favorable long-term results allowing drainage of the serous and bloody discharge without removal of the mold, and reduction of infection rate and the chance of skin graft shearing in McIndoe vaginoplasty. METHODS: We retrospectively reviewed data of 10 consecutive patients with Mayer-Rokitansky-Kuster-Hauser syndrome who underwent McIndoe vaginoplasty between March 2010 and January 2014. We used a specially designed pored polyacetal mold (Figure) in all reconstructed vaginal wounds. The anatomical surgical success was evaluated by physical examination and functional success, which was defined as satisfaction with sex evaluated by patient self-assessed questionnaire. RESULTS: The follow-up period ranged from 1 to 3.5 years. The postoperative mean vaginal length was 9.5 cm in nine patients who used the mold regularly. In all cases in which a pored polyacetal mold was used, skin engraftment was successfully maintained without partial skin graft loss or infection. The subjective patient self-assessed satisfaction evaluation reported a high satisfaction rate. DISCUSSION: The multi-holed polyacetal vaginal mold was designed to perform vaginal irrigation without removal of the mold, allowing drainage of the serous and bloody discharge. This makes it possible to reduce infection rate and maintain successful skin engraftment by reducing the chance of skin graft shearing. The characteristics of polyacetal make it useful as a vaginal mold material as it is lightweight to use, easy to manufacture in accordance with the dimensions of the neovaginal space, and cost-effective. Although a constant follow-up evaluation is required, the pored polyacetal mold is an attractive vaginal mold dressing material to maximize the initial graft uptake, and it can be individually tailored in patients undergoing McIndoe-style vaginoplasty. CONCLUSIONS: The specially designed vaginal mold made up of pored polyacetal is a proper vaginal mold, which could maximize the initial graft uptake, decrease the risk of wound infection, and, therefore, decrease contracture of the neovagina in patients undergoing McIndoe vaginoplasty.

Recent trends in contraceptive use among Korean adolescents: Results from a nationwide survey from year 2013 to 2015.

OBJECTIVE: This study was aimed to evaluate the recent trends in contraceptive use among Korean adolescents. METHODS: Data reviewed were from the 2013-2015 Korean Youth Risk Behavior Web-based Survey, which is a stratified, multistage-sampling designed online-based research project performed annually by the Korean government to ensure a nationally representative sample of Korean adolescence. Eight questions related to the topic of contraception were reviewed for the outcome variables. RESULTS: A total of 212,538 adolescents attending middle school and high school participated in the survey, and 8,755 students among them who were sexually active were included in the study. The percentage of contraceptive use showed a steady increase from 39% in 2013 to 48.7% in 2015; however, the proportion of adolescents who have never used any kind of contraception still remains high. Highly effective methods such as oral contraceptives and intrauterine devices were used by only 10% to 15% of sexually active adolescents. CONCLUSION: The present study demonstrates the status of contraceptive use among Korean adolescents. Our data have the potential to help healthcare providers to formulate policies and develop interventions for encouraging effective contraceptive use among sexually active Korean adolescents.

Efficacy and safety of a 24-day regimen of drospirenone-containing combined oral contraceptive in Korean women.

This study assesses the efficacy and safety of a 24-day regimen of drospirenone-containing combined oral contraceptive, and demonstrates that it is an effective and safe option for contraception, releasing symptom of premenstrual dysphoric disorder and acne in Korean women.

Effects of Hormone Therapy on Serum Lipid Levels in Postmenopausal Korean Women.

OBJECTIVES: This study was conducted to examine the effects of hormone therapy on serum lipid levels in postmenopausal Korean women. METHODS: This retrospective cohort study included 154 healthy postmenopausal Korean women. Seventy-nine women took oral estrogen (conjugated equine estrogen 0.625 mg/day or equivalent), and 75 applied estrogen transdermally using 0.1% 17ß-estradiol gel. Micronized progesterone (MP) was added to 40 women of oral group and 49 women in transdermal group. Serum levels of triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein (a) were measured before, 3 and 6 month after hormone therapy. RESULTS: At baseline, mean body mass index (BMI) were lower (22.76 vs. 23.74 kg/m(2)) and proportion of family history of cardiovascular disease (CVD) (61 vs. 39%) were higher in oral group. In oral group, LDL-C and lipoprotein(a) levels decreased, and triglyceride and HDL-C levels increased significantly after 3 and 6 months. There was no significant change in lipoprotein levels compared to the baseline in transdermal group. There were also no differences with additional MP. Changing pattern of HDL-C during 6 months was significantly different by the route of estrogen administration. CONCLUSION: Oral estrogen therapy might be more beneficial than transdermal estrogen in terms of lipid in postmenopausal Korean women. The estrogen effects are not influenced by adding MP.

Prevalence of metabolic syndrome is higher among non-obese PCOS women with hyperandrogenism and menstrual irregularity in Korea.

BACKGROUND: Hyperandrogenism (HA) has been linked with several components of metabolic syndrome (MetS). Few studies in Asian women have evaluated the important risk factors for and prevalence of MetS according to PCOS subtype. In this study, we investigated differences in metabolic parameters and the prevalence of MetS in two major phenotypic subgroups of PCOS in Korea. Furthermore, we investigated the relationship between HA-associated parameters and MetS. MATERIALS AND METHODS: This cross-sectional observational study was conducted from May 2010 to December 2011 in Korea. A total of 837 females with PCOS, aged 15-40, were recruited from Departments of Obstetrics and Gynecology at 13 hospitals. Of those, 700 subjects with either polycystic ovaries (PCO)+HA+oligomenorrhea/amenorrhea (O) or PCO+O were eligible for this study. MetS was diagnosed according to the modified National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines and the International Diabetes Federation (IDF) criteria. RESULTS: MetS was more prevalent in the PCO+HA+O group (19.7%) than in the PCO+O (11.9%) group. There were statistically significant trends for an increased risk of MetS in the PCO+HA+O group compared to the PCO+O group. After adjustment for age, the odds ratio of MetS was 2.192 in non-obese subjects with PCO+HA+O compared to those with PCO+O, whereas the risk of MetS was not different in obese patients. Multivariate logistic regression analysis showed that high free androgen index and low sex hormone-binding globulin were significantly associated with MetS in non-obese women with PCOS, with odds ratios of 4.234 (95% CI, 1.893-9.474) and 4.612 (95% CI, 1.978-10.750), respectively. However, no associations were detected between MetS and SHBG and FAI in obese PCOS subjects. CONCLUSIONS: Our results indicate that HA and its associated parameters (FAI and SHBG) are significantly associated with MetS in non-obese PCOS subjects, whereas this association was not observed in obese subjects.

Complete phenotypic and metabolic profiles of a large consecutive cohort of untreated Korean women with polycystic ovary syndrome.

OBJECTIVE: To investigate the complete metabolic and phenotypic profiles of a large cohort of untreated, consecutively recruited Korean women with polycystic ovary syndrome (PCOS), for whom a registry for Korean women with PCOS was constructed. DESIGN: Observational study. SETTING: Three infertility clinics and 10 university hospitals. PATIENT(S): Eight hundred sixty-five women with PCOS were recruited using the Rotterdam criteria. INTERVENTION(S): Standardized evaluation protocol and web-based case report form. MAIN OUTCOME MEASURE(S): Metabolic and phenotypic profiles. RESULT(S): The subjects with PCOS mainly consisted of young and nonobese women. The most problematic subjective symptom was menstrual disturbance or infertility, and, on average, the patients seemed to menstruate every 2 months. PCO morphology was observed in 96.5% of the patients. Although few women visited hospitals owing to HA symptoms alone, hirsutism was observed in one-third of the patients (33.9%) and half (47.4%) of the patients had biochemical HA. About one-fifth (20.1%) of the patients had generalized obesity, and one-third (33.2%) had central obesity. Prevalence of dyslipidemia, diabetes, hypertension, and metabolic syndrome were 35.7%, 3.5%, 4.0%, and 13.7%, respectively. Prevalence of prediabetes was 20.8%, and a substantial proportion of additional subjects with normal fasting plasma glucose or oral glucose tolerance tests were identified as having prediabetes by hemoglobin A1C testing. CONCLUSION(S): Our well-defined cohort provided comprehensive estimates of the features of metabolic and phenotypic profiles related to PCOS in Korean women. Further longitudinal follow-up studies are needed to investigate the changes in phenotypic and metabolic markers in this PCOS cohort.

The role of autophagy in follicular development and atresia in rat granulosa cells.

OBJECTIVE: To investigate the involvement of autophagy in folliculogenesis and its correlation with apoptosis. DESIGN: Animal model-based study. SETTING: University medical center. ANIMAL(S): Twenty-one day-old female Sprague-Dawley rats. INTERVENTION(S): Ovaries obtained from established immature rat models primed with pregnant mare serum gonadotropin (PMSG) were used for the induction of follicular development and atresia. Granulosa cells isolated from developing follicles were cultured in serum-free condition with or without follicle-stimulating hormone. MAIN OUTCOME MEASURE(S): Microtubule-associated light-chain protein 3 (LC3) and autophagic vacuoles were used as autophagic markers, and cleaved caspase-3 was used as an apoptotic marker in ovaries and/or granulosa cells. RESULT(S): The LC3 protein was expressed mainly in granulosa cells during all developmental stages. In granulosa cells isolated from PMSG-primed immature rat ovaries, LC3-II expression showed a similar expression pattern to cleaved caspase-3. In addition, granulosa cells of atretic follicles that showed intense cleaved caspase-3 staining also showed intense LC3 immunoreactivity. An in vitro culture experiment revealed that the levels of LC3-II and cleaved caspase-3 proteins were gonadotropin-dependent. The induction and the gonadotropin dependency of granulosa cell autophagy were confirmed by the observation of autophagic vacuoles under transmission electron microscopy. CONCLUSION(S): These preliminary results suggest that autophagy is induced mainly in granulosa cells during folliculogenesis and shows good correlation with apoptosis.

Effects of HMGB-1 overexpression on cell-cycle progression in MCF-7 cells.

High mobility group-1 (HMGB-1) enhances the DNA interactions and possesses a transcriptional activation potential for several families of sequence-specific transcriptional activators. In order to examine the effect of HMGB-1 on the cell cycle progression in MCF-7 cells, the HMGB-1 expression vector was transfected into synchronized MCF-7 cells, and the effect of HMGB-1 overexpression on the cell cycle was examined. The HMGB-1 protein level in the transfected cells increased 4.87-fold compared to the non-transfected cells. There were few changes in the cell cycle phase distribution after HMGB-1 overexpression in the MCF-7 cells. Following the estrogen treatment, the cell cycle progressed in both the HMGB-1 overexpressed MCF-7 and the mock-treated cells. However, a larger proportion of HMGB-1 overexpressing MCF-7 cells progressed to the either S or G2 phase than the mock-treated cells. The mRNA levels of the cell cycle regulators changed after being treated with estrogen in both the HMGB-1 overexpressing MCF-7 and the mock-treated cells, but the changes in the expression level of the cell cycle regulator genes were more prominent in the HMGB-1 overexpressing MCF-7 cells than in the mock-treated cells. In conclusion, HMGB-1 overexpression itself does not alter the MCF-7 cell cycle progression, but the addition of estrogen to the HMGB-1 overexpressing MCF-7 cells appears to accelerate the cell cycle progression.

Effects of activation timing on the fertilization rate and early embryo development in porcine ROSI procedure.

PURPOSE: This study was undertaken to evaluate the optimal exposure time for nuclear envelope breakdown (NEBD) after injection of a round spermatid and to investigate the effect of oocyte activation timing on the fertilization rate and early embryo development in porcine round spermatid injection procedure. METHODS: Injected oocytes were fixed at 0.5, 1, 2, 3, and 4 h before activation, and NEBD state was examined. The three groups of oocytes were activated before and after the injection of spermatid using a single direct current pulse (100 V/mm, 50 micros): group 1) at 2 h before the injection (pre), group 2) within 0.5 h after the injection (immediate), and group 3) at 2 h after the injection (post). Activated oocytes were cultured and pronucleus formation and blastocyst development was evaluated at 15-18 h and 7-8 days after the injection, respectively. RESULTS: The proportion of oocytes with NEBD significantly increased in the groups with over 2 h of exposure time (p < 0.05) and oocyte with premature chromosome condensation began to appear 3 h after the injection. Normal fertilization and development rate to the blastocyst stage were significantly higher in the post group than in those of the pre or immediate group (p < 0.05). CONCLUSION: The optimal exposure time for NEBD is 2 h after the injection, and activation in 2 h after round spermatid injection improved the normal fertilization and early embryo development rate.