Human Endometrium Derived Induced Pluripotent Stem Cells Are Amenable to Directed Erythroid Differentiation

BACKGROUND@#A protocol for using human endometrium derived induced pluripotent stem cells (iPSCs) to derive hematopoietic and erythroid lineages will be elaborated, through a two-phase culture system. @*METHODS@#Discarded endometrial tissues were obtained from women receiving hysterectomy in their 4th to 5th decade due to benign uterine conditions. pCE-Sox2, Oct4, Klf4, L-Myc and Lin28 episomal vectors were used to electrotransfect the endometrial stromal cells. The first 8 days involves commitment to hematopoietic stem cells through embryoid body with robust expansion on murine bone marrow stromal cells. The second phase involves feeder free conditions with hydrocortisone, stem cell factor, interleukin-3, and recombinant EPO. After 22 days of feeder free culture, the expression profiles of CD235a+ , CD34+ , CD43+ and CD 71+ were analyzed by flow cytometry and Wright-Giemsa staining for differential counting. The oxygen carrying capacity of cultured RBCs was measured using a hemoxanalyser. @*RESULTS@#As a result of inducing these cells via co-culture with murine stromal fibroblasts, all endometrium derived iPSCs were differentiated into erythroblasts with a stable yield of approximately 80% for polychromatic and orthochromatic normoblasts. The protocol for complete induction of erythroid lineage cells starting from human endometrial tissue via iPS cells has been optimized. @*CONCLUSION@#Successful directed erythroid differentiation has occurred from human endometrium-derived iPS cells. A comprehensive process of actually deriving iPS cells using discarded surgical hysterectomy specimens to the erythroid fate has significance in that the scope of using human iPSC cell lines for tissue regeneration could be expanded in the future.

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 in the 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.

Delayed postpartum regression of theca lutein cysts with maternal virilization: A case report / 대한생식의학회지

Theca lutein cysts are rare, benign lesions responsible for gross cystic enlargement of both ovaries during pregnancy. This condition is also termed hyperreactio luteinalis. Elevated human chorionic gonadotropin (hCG) levels or states of hCG hypersensitivity seem to promote these changes, which in up to 30% of patients produce clinical signs of hyperandrogenism. Given the self-limiting course of theca lutein cysts, which are subject to spontaneous postpartum resolution, conservative treatment is the mainstay of patient management. Described herein is a rare case of theca lutein cysts with maternal virilization that failed to regress by 9 months after childbirth. Surgical intervention was eventually undertaken, necessitated by adnexal torsion.

Administration of red ginseng regulates microRNA expression in a mouse model of endometriosis / 대한생식의학회지

Red ginseng (RG) exerts anti-inflammatory, anti-proliferative, and immunomodulatory effects on endometriosis through the regulation of microRNA (miRNA) expression. It may also ameliorate endometriosis by affecting the expression of multiple miRNAs simultaneously, rather than acting on a single miRNA at a given time. Since studies on the overall effects of RG on endometriosis via the regulation of miRNA expression are lacking, the current study aimed to explore the global effect of RG on miRNA expression in a mouse model of endometriosis. Methods: To establish the mouse model, the uterine horn of donor mice was implanted into the lateral side of the recipients’ peritoneum, followed by vehicle or RG treatment for 8 weeks. Results: To confirm the effects of RG on the established mouse model, the size of the implanted uterus was measured; it was found to be lower in mice from the RG group than in mice from the control group. miRNA expression profiles in the implanted uterus of the mouse model of endometriosis after vehicle or RG administration were analyzed using microarray technology. Thereafter, seven candidate miRNAs and 125 candidate genes (miRNA targets) were identified through a bioinformatics analysis. Conclusion: The present findings suggest that RG regulates the expression of multiple miRNAs and mRNAs, thereby alleviating endometriosis in a mouse model of the disease.

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 in the 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.

A New Thermo-Responsive Hyaluronic Acid Sol-Gel to Prevent Intrauterine Adhesions after Hysteroscopic Surgery: A Randomized, Non-Inferiority Trial

Purpose@#To investigate the efficacy and safety of a newly developed thermo-responsive sol-gel, ABT13107, for reducing the formation of intrauterine adhesions (IUAs) after hysteroscopic surgery. @*Materials and Methods@#In this multicenter, prospective, randomized trial (Canadian Task Force classification I), 192 women scheduled to undergo a hysteroscopic surgery at one of the eight university hospitals in South Korea were randomized into the ABT13107 group or the comparator (Hyalobarrier ® ) group in a 1:1 ratio. During hysteroscopic surgery, ABT13107 or Hyalobarrier® was injected to sufficiently cover the entire intrauterine cavity. @*Results@#The patients returned to their respective sites for safety assessments at postoperative weeks 1 and 4 and for efficacy assessments at postoperative week 4. The post-surgery incidence of IUAs was 23.4% in the ABT13107 group and 25.8% in the comparator group; this difference met the criteria for ABT13107 to be considered as not inferior to the comparator. No differences were found in the extent of adhesions, types of adhesions, or the cumulative American Fertility Society score between the two treatment groups. Most adverse events were mild in severity, and no serious adverse events occurred. @*Conclusion@#ABT13107, a new anti-adhesive barrier containing hyaluronic acid, was not inferior to the highly viscous hyaluronic acid anti-adhesive barrier, Hyalurobarrier® in IUA formation after hysteroscopic surgery (Clinical trial registration No. NCT 04007211).

Operative hysteroscopy-assisted pregnancy termination after failed surgical abortion in missed abortion of woman with complete septate uterus

Diagnosis and treatment of endometriosis

Endometriosis is a common gynecological condition characterized by chronic pelvic pain, dysmenorrhea and subfertility. However, the pathophysiology of the disease remains unclear and accurate non-invasive diagnostic methods are unavailable. Although clinical symptoms, serum biomarkers, and imaging studies, such as transvaginal ultrasonography and magnetic resonance imaging are useful diagnostic aids, laparoscopy remains the gold standard for the diagnosis of endometriosis. The treatment of endometriosis should be individualized and a multi-disciplinary approach is recommended based on degree of disease-associated symptoms, patient characteristics and preferences, reproductive plans, and desired quality of life. Surgical management is effective for subfertility, chronic pain, and ovarian endometriomas. The principle of surgery is removal of all ectopic endometrial lesions while ensuring that no lesions are missed. Currently, numerous medical treatment options are available to manage endometriosis-associated symptoms; however, all modalities are suppressive rather than curative. Further studies are needed to clarify the exact pathophysiology of endometriosis to enable the development of non-invasive diagnostic tools for early detection and to indicate potential therapeutic targets for this chronic and frustrating disease.

Polycystic ovarian morphology is associated with primary dysmenorrhea in young Korean women

OBJECTIVE: This study was aimed at identifying a correlation between polycystic ovarian morphology (PCOM) and the severity of primary dysmenorrhea in young Korean women. METHODS: A total of 592 patients who visited a tertiary hospital from March 2008 to March 2015 for dysmenorrhea were examined. After excluding those with secondary causes of menstrual pain (for example, myoma, adenomyosis, endometriosis, and pelvic inflammatory disease), 361 women were recruited and retrospectively analyzed. Severe dysmenorrhea was defined as a visual analog scale (VAS) score ≥6. RESULTS: The mean patient age was 23.0±4.0 years, the average menstrual cycle length was 34.4±23.7 days, and the average pain intensity was VAS 6.7±0.1 at baseline. PCOM was assessed by ultrasound in 54 women (15%). Patients with severe menstrual pain were more likely to have irregular menstrual cycles (P=0.03) and heavy menstrual flow (P=0.01) than those with mild menstrual pain. After adjusting for weight, height, menstrual cycle interval, and menstrual flow in the logistic regression analysis, PCOM (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.05–4.97; P=0.04) and heavy menstrual flow (OR, 1.85; 95% CI, 1.05–3.28; P=0.04) were found to be significant independent factors influencing pain. CONCLUSION: Our study shows that PCOM may have a correlation with the severity of primary dysmenorrhea. Since PCOM may play a role in the development of menstrual pain, patients with PCOM should be under active surveillance with resources for prompt pain management readily available. It may also be necessary to further investigate the molecular mechanisms of pain development in primary dysmenorrhea.

Experiences of localization and removal of non-palpable subdermal contraceptive implants with ultrasound

OBJECTIVE: The aim of this study was to present experiences in localization and removal of non-palpable subdermal contraceptive implants with ultrasonography. METHODS: Medical records from January 1, 2016, to April 30, 2018, were retrospectively reviewed for 21 patients who were referred to a single institution and had an impalpable implant despite following the removal instruction. In all the cases, more than one attempt was made to remove the implant before referral. The rod was detected using radiography and ultrasonography. In all the cases, localization of the single implant was achieved with ultrasonography. The distal depth of the rod was measured, and skin marking was made following the echogenicity. The implants were subsequently removed under anesthesia. RESULTS: In 18 cases, the rods were localized using ultrasonography and successfully removed under local anesthesia. In the other three cases, removal with local anesthesia failed. Although the rod was detected successful with ultrasonography, the implants were removed under general anesthesia in the operating room. The depth from skin to rod, measured with ultrasonography, was >12.0 mm in all the cases and located deep in the muscular layer in the failure cases. The depth of the implants positively correlated with the time spent for removal (r=0.525; P=0.015). CONCLUSION: High frequency ultrasonography is a highly accurate tool for localization and measurement of the skin-to-rod depth. It is also useful for removing non-palpable implants. If the depth of the implant is >12.0 mm, removal of the implant in the operating room under general anesthesia is recommended.

Diagnosis of an indistinct Leydig cell tumor by positron emission tomography-computed tomography

A 51-year-old perimenopausal female patient presented with hirsutism and voice thickening which was started approximately one and a half years ago. Her initial hormone assay revealed elevated plasma testosterone, 5a-dihydrotestosterone, and dehydroepiandrosterone (DHEA) levels and therefore androgen-secreting tumor was first suspected. However, the lesion was inconspicuous on transvaginal sonography, abdominal-pelvic computed tomography (CT) scan, and pelvic magnetic resonance (MRI) imaging. Consequently, 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT was performed, which localized the lesion as a focal FDG uptake within the right adnexa. Total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed, and although visible gross mass lesions were not observed intraoperatively, pure Leydig cell tumor was pathologically confirmed within the right ovary. Plasma testosterone, 5a-dihydrotestosterone, and DHEA levels were normalized postoperatively. Clinical signs of virilization were also significantly resolved after 3-months of follow-up.

Diagnosis and treatment of endometriosis

Endometriosis is a common gynecological condition characterized by chronic pelvic pain, dysmenorrhea and subfertility. However, the pathophysiology of the disease remains unclear and accurate non-invasive diagnostic methods are unavailable. Although clinical symptoms, serum biomarkers, and imaging studies, such as transvaginal ultrasonography and magnetic resonance imaging are useful diagnostic aids, laparoscopy remains the gold standard for the diagnosis of endometriosis. The treatment of endometriosis should be individualized and a multi-disciplinary approach is recommended based on degree of disease-associated symptoms, patient characteristics and preferences, reproductive plans, and desired quality of life. Surgical management is effective for subfertility, chronic pain, and ovarian endometriomas. The principle of surgery is removal of all ectopic endometrial lesions while ensuring that no lesions are missed. Currently, numerous medical treatment options are available to manage endometriosis-associated symptoms; however, all modalities are suppressive rather than curative. Further studies are needed to clarify the exact pathophysiology of endometriosis to enable the development of non-invasive diagnostic tools for early detection and to indicate potential therapeutic targets for this chronic and frustrating disease.

Current medical treatment of uterine fibroids

Uterine fibroids (leiomyomas or myomas), benign monoclonal tumors, are the most common benign tumors in women. Heavy or prolonged menstrual bleeding, abnormal uterine bleeding, resultant anemia, pelvic pain, infertility, and/or recurrent pregnancy loss are generally associated with uterine fibroids. Although curative treatment of this tumor relies on surgical therapies, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. The aim of this review is to provide available and emerging medical treatment options for symptomatic uterine fibroids. Literature review and consensus of expert opinion. Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow-up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Treatment options for symptomatic uterine fibroids — include medical, surgical, and radiologically guided interventions. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Currently, gonadotrophin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRMs) are the most effective medical therapies, with the most evidence to support their reduction of fibroid volume and symptomatic improvement in menstrual bleeding. The choice of treatment depends on the patient's personal treatment goals, as well as efficacy and need for repeated interventions.

Combination of clinical and laboratory characteristics may serve as a potential diagnostic marker for torsion on mature cystic teratomas

OBJECTIVE: The objective of this study was to evaluate clinical and laboratory characteristics of torsion on mature cystic teratomas (MCTs). In addition, we examined whether these factors could be helpful in diagnosing MCT torsion. METHODS: A retrospective medical record review was conducted for 384 patients who had undergone surgery and histologically verified ovarian MCTs at single university hospital between July 2006 and May 2017. Patients with or without torsion groups were compared with respect to clinical presentation, laboratory findings and surgical course. In addition, statistically significant indicators of the factors were additionally evaluated for diagnostic value. RESULTS: White blood cell (WBC) count, neutrophil count, neutrophil to lymphocyte (N/L) ratio, and tumor size were higher in the torsion group (n=24) than in the control group (n=360; P≤0.005 for all). The age was younger in the torsion group than in the control (P=0.009). In the area under the curve (AUC) of the 5 factors obtained by univariate and multivariate logistic regression, the age was 0.657, the WBC count was 0.838, the neutrophil count was 0.806, the N/L ratio was 0.725, and the cyst size was 0.705. Receiver operating characteristic analysis indicated that the AUC for the combined use of age, WBC count, neutrophil count, N/L ratio, and tumor size was 0.898 (95% confidence interval, 0.833–0.962; P < 0.001). CONCLUSION: The combined measurement of age, WBC count, neutrophil count, N/L ratio, and tumor size may be used as a potential diagnostic marker for the torsion on MCTs.

In vitro fertilization outcome in women with diminished ovarian reserve

OBJECTIVE: This study aimed to identify factors that affect in vitro fertilization (IVF) outcomes in women with diminished ovarian reserve (DOR). METHODS: We reviewed 99 IVF cycles in 52 women with DOR between September 2010 and January 2015. DOR was defined as serum anti-Müllerian hormone level of <1.1 ng/dL or serum follicle-stimulating hormone level of ≥20 mIU/mL. Total 96 cycles in 50 patients were evaluated after excluding fertility preservation cases. RESULTS: The clinical pregnancy rate was 11.5% per cycle, and the total cancellation rate was 34.4%. Clinical pregnancy rate was significantly associated with the antral follicle count and the cause of the DOR. Age, serum anti-Müllerian hormone and follicle-stimulating hormone levels, antral follicle count, peak estradiol level, and the cause of DOR were significantly associated with cycle cancellation. However, history of previous ovarian surgery remained as a significant factor of clinical pregnancy (model 1: odds ratio [OR] 10.17, 95% confidence interval [CI] 1.46 to 70.84, P=0.019; model 2: OR 10.85, 95% CI 1.05 to 111.71, P=0.045). In cancellation models, idiopathic or previous chemotherapy group showed borderline significance (model 1: OR 3.76, 95% CI 0.83 to 17.04, P=0.086; model 2: OR 3.15, 95% CI 0.84 to 11.84, P=0.09). CONCLUSION: DOR caused by previous ovarian surgery may show better pregnancy outcome, whereas that caused by chemotherapy could significantly increase the cycle cancellation rate. Furthermore, patients with DOR who previously received gonadotoxic agents may show reduced efficacy and increased risk of IVF cycle cancellation.

Migration of a contraceptive subdermal device into the lung

A single-rod subdermal contraceptive implant is usually located around the insertion site, has been usually known to migrate within less than 2 cm of the insertion site and the true migration over 2 cm has been rarely reported. We report a case of migrated radiopaque subdermal contraceptive implant into lung in a 37-year-old woman. On conducted chest computed tomography, subdermal contraceptive implant was in subsegmental branch in left posterior basal segment of lung. Removal of subdermal contraceptive implant in left posterior basal segment of lung by mini-thoracotomy was performed by a chest surgeon. Complications with insertion and removal of subdermal contraceptive implant are rare in the hands of medical professionals familiar with the techniques and these procedures should only be undertaken by those with relevant training. The migration over 2 cm should not occur if the correct subdermal insertion procedure is followed and carried out by a properly trained individual.

Common Causes of Postmenopausal Bleeding in Korean Women: 10-Year Outcomes from a Single Medical Center

The common causes of postmenopausal bleeding (PMB), according to the data from the western world, are atrophy, hormone replacement therapy (HRT), endometrial cancer, etc. We conducted a retrospective study to assess whether the causes of PMB in Korean postmenopausal women are similar to those already known. This retrospective study used 10-year medical records (March 2005 to December 2014) of 792 PMB women in the Yonsei University Health System. The data were divided into 2 categories by 5-year intervals to compare the differences between the 2 periods. The most common cause of PMB in Korean women was atrophy (51.1%). Polyps and HRT were the second, followed by anticoagulant medications, cervical cancer, and endometrial cancer. The proportion of patients with cervical cancer significantly decreased during the second half of the decade (8.7% vs. 5.2%; P = 0.048). Although no significant change was noted for HRT, its rank was higher during the latter 5-year period. Only the most common cause of PMB was the same as the conventional data. Interestingly, the proportion of patients with cervical cancer decreased during the latter half of the decade, reflecting the changes in the nation's cancer prevalence rate, while the use of HRT increased.

The Level of Serum and Urinary Nephrin in Normal Pregnancy and Pregnancy with Subsequent Preeclampsia

PURPOSE: The aim of this study was to evaluate serum and urinary nephrin levels of normal pregnancy to establish a standard reference value and to compare them with patients who subsequently developed preeclampsia (PE). MATERIALS AND METHODS: In this prospective study, 117 healthy singleton pregnancies were enrolled between 6 to 20 weeks of gestation at 2 participating medical centers during October 2010 to March 2012. Urine and serum samples were collected at the time of enrollment, each trimester, and at 4 to 6 weeks postpartum. Enzyme-linked immunosorbent assay for nephrin was performed and samples from patients who subsequently developed PE were compared to the normal patients. RESULTS: Of 117 patients initially enrolled, 99 patients delivered at the study centers and of those patients, 12 (12.1%) developed PE at a median gestational age of 34⁺⁴ weeks (range 29⁺⁵–36⁺⁶). In the normal patients (n=68), serum nephrin level decreased and urinary nephrin level increased during the latter of pregnancy. In 12 patients who subsequently developed PE, a significant rise in the 3rd trimester serum and urinary nephrin levels, compared to the controls, was observed (p<0.001), and this increase occurred 9 days prior to the onset of clinical disease. CONCLUSION: As the onset of PE was preceded by the rise in the serum and urinary nephrin in comparison to normal pregnancy, serum and urinary nephrin may be a useful predictive marker of PE.

Clinical use of oral contraceptives

Since first introduction of oral contraceptive pills in 1960, with increased women's right of sexual decision, oral contraceptives had been used widely around the globe as a highly effective and safe contraceptive method. The physiological mechanisms of oral contraceptives were a reduced maturation of ovarian follicles and blocked ovulation to fertile women. Also, oral pills induce uterine endometrial decidualization, thickening of cervical mucus, disturbance of intrauterine sperm movement and embryo implantation. However, in addition to providing effective reversible contraception to fertile women, oral contraceptive pills offer various non-contraceptive benefits to numerous conditions. In this review, we summarize the list of currently available oral contraceptive pills in Korea and discuss non-contraceptive indications of oral contraceptives pills.

The Prognostic Value of Individual Adhesion Scores from the Revised American Fertility Society Classification System for Recurrent Endometriosis

PURPOSE: This study aimed to evaluate the prognostic value of each component of the revised American Fertility Society (rAFS) classification system for the first recurrence of endometriosis after conservative laparoscopy. MATERIALS AND METHODS: As this was a retrospective cohort study, data were collected by reviewing medical records. A total of 379 women ages 18 to 49 years were included. Women who underwent conservative laparoscopy with histologic confirmation of endometriosis at Gangnam Severance Hospital between March 2003 and May 2010 were included. Individual components of the rAFS classification system as well as preoperative serum CA-125 levels were retrospectively analyzed to assess their prognostic values for recurrence of endometriosis. RESULTS: Of 379 patients, 80 (21.2%) were found to have recurrence of endometriosis. The median duration of follow-up was 19.0 months, and the mean age at the time of surgery was 31.8+/-6.7 years. In endometriosis of advanced stage, younger age at the time of surgery, bilateral ovarian cysts at the time of diagnosis, a rAFS ovarian adhesion score >24, and complete cul-de-sac obliteration were independent risk factors of poor outcomes, and a rAFS ovarian adhesion score >24 had the highest risk of recurrence [hazard ratio=2.948 (95% CI: 1.116-7.789), p=0.029]. CONCLUSION: Our results suggest that of the rAFS adnexal adhesion scores, the ovarian adhesion score rather than the tubal adhesion score was associated with a significantly increased risk of recurrent endometriosis. The preoperative serum CA-125 level may be also a significant prognostic factor for recurrence, as known. However, it seemed to only have borderline significance in affecting recurrence in the current study.