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To evaluate the safety and effectiveness of recombinant human follicle-stimulating hormone (rhFSH [Follitrope™]) in infertile women undergoing in vitro fertilization (IVF). To identify predictors of ovarian response that induce optimal clinical outcomes. This multicenter prospective study enrolled infertile women who were scheduled to undergo IVF after ovarian stimulation with rhFSH (Follitrope™) following the gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist protocol. Predictive factors for ovarian response were identified in the GnRH antagonist group based on the number of oocytes retrieved. A total of 516 infertile women were enrolled, among whom 136 (except one who withdrew before administration) received rhFSH using the GnRH agonist protocol and 379 using the antagonist protocol. The mean number of oocytes retrieved was 13.4 in the GnRH agonist group and 13.6 in the GnRH antagonist group. The clinical pregnancy rates were 32.3% (30/93) and 39.9% (115/288) in the GnRH agonist and antagonist groups, respectively. The incidence of ovarian hyperstimulation syndrome was 1.8% and 3.4% in the GnRH agonist and antagonist groups, respectively. No other significant safety risks associated with rhFSH administration were identified. Body mass index, basal serum FSH and anti-Müllerian hormone levels, and antral follicle count were identified as predictors of ovarian response by multiple regression with backward elimination, and the final regression model accounted for 26.5% of the response variability. In real-world practice, rhFSH (Follitrope™) is safe and effective in inducing ovarian stimulation in infertile women. Patient characteristics identified as predictors can be considered to be highly related to optimal clinical outcomes.

Objective To investigate the correlation between bladder wall thickness (BWT) measured by ultrasonography and lower urinary tract dysfunction (LUTD) in patients with lower urinary tract symptoms (LUTS). Methods Forty-eight women with LUTS who underwent urodynamic study and BWT by ultrasonography as outpatients were studied. We assessed LUTS during a medical examination by interview. The thinnest part of the bladder wall was measured by a transabdominal ultrasonography. We excluded patients who had visited another hospital previously because we did not know what treatment they had received, including medications, behavioral therapy, or other treatments. We constructed receiver operating characteristic (ROC) curves for diagnosis of LUTD and also determined reliable BWT criteria by calculating the area under the curve. Statistical analyses were performed using the Kolmogorov-Smirnov method and Student's t-test. Results The mean age, body mass index, and duration of symptoms were 59.9±9.7 years, 26.06±3.4 kg/m2, and 53.4±38.2 months, respectively. Urodynamic study parameters (Valsalva leak point pressure, maximal urethral closure pressure, functional length, and postvoid residual volume) were lower in patients with BWT

PURPOSE Progesterone resistance is thought to be a major factor that contributes to progression of endometriosis. However, it is not clear what causes progesterone resistance in endometriosis. This study aimed to assess whether cytokines or peritoneal fluid can affect progesterone receptor (PR) expression in endometrial cells and to verify whether PR expression is reduced in endometriosis. MATERIALS AND METHODS The PR-B/A ratio was measured via real-time polymerase chain reaction after in vitro culture, in which endometrial cells were treated with either tumor necrosis factor-alpha (TNF-α), interleukin-1 beta, or peritoneal fluid obtained from women with advanced-stage endometriosis. Immunohistochemistry was performed to compare PR-B expression between eutopic and ectopic endometrial tissues from women with and without advanced-stage endometriosis. RESULTS The PR-B/A ratio was significantly decreased by treatment with either TNF-α (p=0.011) or peritoneal fluid from women with advanced-stage endometriosis (p=0.027). Immunoreactivity of PR-B expression was significantly lower during the secretory phase than during the proliferative phase in endometrial tissues from control subjects (p

The transobturator tape (TOT) method is the recent minimally invasive midurethral sling surgery. The TOT method was invented to reduce complication rate of surgical technique for female stress urinary incontinence. Pelvic bleeding following TOT procedure, although extremely rare, could be occurred. We presented three cases which treat pelvic arterial bleeding after midurethral sling (TOT and tension-free vaginal tape Secur) surgery via pelvic artery embolization. Therefore we report our cases with brief review of the literature.

Study question Does interleukin-32 (IL-32) play a role in the pathogenesis of endometriosis? Summary answer IL-32 might be involved in the pathogenesis of endometriosis through increased viability, proliferation and invasion of endometrial cells. What is known already Endometriosis is characterized as a chronic inflammatory disease and several proinflammatory cytokines are suggested to be involved in its pathogenesis and pathophysiology. IL-32, recognized as a new proinflammatory cytokine and a strong inducer of other proinflammatory cytokines, has been shown to serve as a key modulator in several chronic inflammatory diseases. Study design, size, duration This study included comparison of IL-32 levels in the peritoneal fluids between women with and without endometriosis, in-vitro experiments using Ishikawa cells and endometrial stromal cells (ESCs), and experiments on IL-32 transgenic mice and wild-type mice with induced endometriosis. Participants/materials, setting, methods IL-32 levels in the peritoneal fluids were measured using enzyme-linked immunosorbent assays. Cell viability, expression of proliferating cell nuclear antigen (PCNA), and cellular invasiveness were analyzed following in-vitro treatment of Ishikawa cells and ESCs with recombinant IL-32 alpha (α) and gamma (γ). Ectopic endometriotic lesions were compared between IL-32 transgenic mice and wild-type mice after autologous endometrial transplantation with immunohistochemistry for Ki-67 antigen and PCNA. Main results and the role of chance The peritoneal fluid concentration of IL-32 was significantly higher in patients with advanced stage endometriosis compared with the controls. In-vitro treatment with IL-32 α and γ caused significant increases in cellular viability, PCNA expression, and invasiveness in Ishikawa cells and ESCs. The IL-32 transgenic mice had a significantly larger size of the ectopic endometrial lesions with higher expression of Ki-67 antigen and PCNA compared with wild-type mice. Large scale data N/A. Limitations, reasons for caution It is still unclear whether IL-32 is a main regulator, or one of several downstream proinflammatory cytokines, causing establishment and/or progression of endometriosis. Wider implications of the findings Further investigation on IL-32 signaling pathways may contribute to development a more effective treatment of endometriosis. Study funding/competing interest(s) This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C1682). None of the authors has anything to disclose.

This study was performed to investigate the effect of of transdermal testosterone gel (TTG) on controlled ovarian stimulation (COS) and IVF outcomes and ovarian morphology according to pretreatment duration in poor responders. A total of 120 women were recruited for this pilot study. They were randomized into control, 2 weeks, 3 weeks or 4 weeks TTG treatment groups. For three TTG treatment groups, 12.5 mg TTG was applied daily for 2 weeks, 3 weeks or 4 weeks in preceding period of study stimulation cycle. After 3 weeks of TTG pretreatment, significant increase of antral follicle count (AFC) and significant decreases of mean follicular diameter (MFD) and resistance index (RI) value of ovarian stromal artery were observed (p=0.026, p

Type 1 citrullinemia (CTLN1) is an autosomal recessive inherited metabolic disorder caused by anargininosuccinicnate synthetase deficiency. The patient was a 38-year-old Korean woman who is a carrier for CTLN1 and her first baby was diagnosed with CTLN1. Preimplantation genetic diagnosis (PGD) for CTLN1 in day 3 embryos using polymerase chain reaction was performed for live birth of healthy baby who is no affected with CTLN1. One unaffected blastocyst was transferred. This resulted in a clinical pregnancy and the live birth of healthy male twin. They were confirmed to be unaffected with CTNL1 by post natal diagnosis. This is the first case report of the use of PGD for CTNL1.

Objective To identify the most important factor in predicting ovarian reserve after laparoscopic ovarian cystectomy and to evaluate whether there is any difference in the postoperative decline of ovarian reserve between women with endometrioma and those with other benign ovarian cysts. Design Prospective cohort study. Setting University hospital. Patient(s) A total of 100 women who had undergone laparoscopic ovarian cystectomy for endometrioma (n = 68) or other benign ovarian cysts (n = 32). Intervention(s) Serum antimullerian hormone (AMH) levels measured by enzyme immunoassay preoperatively and at 3 months after surgery. Main Outcome Measure(s) Rate of AMH decline after surgery and follicle numbers retained in cystectomy specimens. Result(s) Serum AMH levels were obviously decreased at 3 months after the surgery (4.97 ± 2.83 vs. 3.33 ± 2.08 ng/mL, mean ± standard deviation). Adjusting for several parameters, we could see that bilaterality of the ovarian cyst was the only significant factor in predicting the rate of postoperative decline of AMH levels. The rate of AMH decline did not differ between the endometrioma group and the other benign ovarian cyst group. Conclusion(s) Bilaterality of the ovarian cyst is the only significant factor in predicting the rate of decline of AMH level after laparoscopic ovarian cystectomy. The rate of decline of AMH levels after surgery was similar between the endometrioma group and the other benign ovarian cyst group.

This study was performed to investigate the effect of peroxisome proliferators activated receptor-γ (PPAR-γ) ligand, pioglitazone, on production of regulated upon activation normal T-cell expressed and secreted (RANTES) and in vitro fertilization (IVF) outcome in infertile patients with endometriosis. Sixty-four infertile patients with stage III or IV endometriosis undergoing IVF were randomly allocated to the study or the control group. The long protocol of GnRH agonist (GnRH-a) was used for controlled ovarian stimulation (COS) in all patients. Patients in the study group were treated with pioglitazone at a dose of 15 mg/day orally from the starting day of GnRH-a treatment to the day of hCG injection. Blood samples were drawn for serologic assay of RANTES on the first day of GnRH-a treatment and the day of hCG injection. There were no differences between the study and control groups in patient characteristics. There were also no differences between the two groups in COS duration, and the numbers of retrieved oocytes, fertilized oocytes and embryos transferred. The clinical pregnancy rate per cycle was higher in the study group, but this difference was not statistically significant. However, embryo implantation rate was significantly higher in the study group of 12.5% compared with 8.6% in the control group (P

This study was performed to investigate the expression of cathepsin B mRNA and protein in eutopic and ectopic endometrial tissues of patients with endometriosis and in normal endometrial tissues and to clarify the association between the cathepsin B expression and endometriosis. A total of 40 women with histologically confirmed endometriosis were recruited for study group. For controls, 20 women undergoing operative treatment for uterine myoma, cervical intraepithelial neoplasia (CIN) or benign gynecologic conditions other than endometriosis were recruited. Eutopic endometrial tissues of both groups and ectopic endometrial tissue of study group were collected during the operations. We employed real time reverse transcriptase - polymerase chain reaction (RT-PCR) to quantify mRNA levels of cathepsin B in these tissues. Then, we performed western blot analysis to measure the protein levels of cathepsin B. The expressions of cathepsin B mRNA and protein were significantly higher in both eutopic and ectopic endometrial tissues of women with endometriosis than in endometrial tissues of controls. These data suggest that the higher expression of cathepsin B in the endometrial tissues might be associated with the development of endometriosis. In addition, eutopic endometrium itself with higher expression cathepsin B may play a pivotal role in the histogenesis of endometriosis.

Objective To evaluate the efficacy and safety of dienogest treatment in patients who had received dienogest for 12 months or more to treat endometriosis. Methods We analyzed the clinical data of 188 women with endometriosis who had been treated with 2 mg of dienogest once a day for 12 months or more at a single institute. We evaluated changes in endometriosis-associated pain and endometrioma size, recurrence rate, and adverse events following dienogest administration. Bone mineral density (BMD) was measured in patients who were prescribed dienogest for more than 18 months. Results Pain was significantly reduced at 12 months after dienogest medication. In those treated with dienogest due to recurrent endometrioma, the size of the endometrioma was significantly decreased at the 12-month and 18-month follow-ups. We found only one case of sonographic recurrence during dienogest administration among those who were treated postoperatively to prevent recurrence (1 of 114, 0.9%). The most common adverse drug reaction was uterine bleeding (3.2%), and other adverse events were generally tolerable and associated with low discontinuation rates (5.2%). Among the 50 patients in whom BMD was measured, 10 patients (20%) had a Z-score below the expected range for age. Conclusion The administration of dienogest for a year or more seems to be highly effective in preventing recurrence after surgery, reducing endometriosis-associated pain, and decreasing the size of recurrent endometrioma, with a favorable safety and tolerability profile. However, BMD should be checked in patients on long-term medication due to possible bone loss in some women.

Objective To investigate whether levothyroxine (LT4) treatment has beneficial effects on IVF results and pregnancy outcome in infertile patients with subclinical hypothyroidism undergoing IVF/intracytoplasmic sperm injection (ICSI). Design Prospective, randomized trial. Setting University-affiliated infertility clinic. Patient(s) A total of 64 infertile patients with subclinical hypothyroidism, defined as an elevated serum TSH level associated with a normal free T4 level and without frank symptoms of hypothyroidism. Intervention(s) Patients were randomized into an LT4 treatment group or control group. For the LT4 treatment group, 50 μg LT4 was administered from the first day of controlled ovarian stimulation for IVF/ICSI. Main Outcome Measure(s) Results of IVF and pregnancy outcome. Result(s) There were no differences in patient characteristics between the two groups. Total dose and days of recombinant human FSH used for controlled ovarian stimulation were also similar. The number of grade I or II embryos was significantly higher in the LT4 treatment group than in the control group. There was no significant difference in the clinical pregnancy rate per cycle between the two groups. However, the miscarriage rate was significantly lower in the LT4 treatment group than in the control group. Embryo implantation rate and live birth rate were significantly higher in the LT4 treatment group. In the control group, both thyroid peroxidase antibody and thyroglobulin antibody levels were significantly higher in the miscarried subgroup than in the delivered subgroup. Conclusion(s) LT4 treatment can improve embryo quality and pregnancy outcome in subclinical hypothyroid women undergoing IVF/ICSI.

Objective: To investigate the effectiveness of treatment with transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) using GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI). Design: Prospective randomized controlled trial. Setting: University-affiliated infertility clinic. Patient(s): A total of 110 low responders, who were defined as patients who failed to produce %3 follicles with a mean diameter of R16 mm with the result that %3 oocytes were retrieved despite the use of a high gonadotropin dose (>2,500 IU) in a previous failed IVF/ICSI cycle. Intervention(s): Patients were randomized into TTG pretreatment group or control group. For TTG pretreatment group, 12.5 mg TTG were applied daily for 21 days in the cycle preceding COS for IVF. Main Outcome Measure(s): COS results and IVF outcome. Result(s): There were no differences in patients’ characteristics between the two groups. Total dose and days of rhFSH used were significantly fewer in the TTG pretreatment group than in the control group. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the TTG pretreatment group. Embryo implantation rate and clinical pregnancy rate per cycle initiated also were significantly higher in the women pretreated with TTG. No patient reported adverse effects attributed to TTG use. Conclusion(s): TTG pretreatment might be beneficial in improving both response to COS and IVF outcome in low responders undergoing IVF/ICSI. (Fertil Steril� 2011;95:679‐83. � 2011 by American Society for Reproductive Medicine.)

BACKGROUND: P21-activated kinase I (PakI) integrates various signaling pathways that are vital to cell survival and function. This study was performed to evaluate whether sex steroids may regulate the expression of Pak I in endometrial cells as well as whether its expression is increased in the eutopic endometrium of women with endometriosis. METHODS: Following in vitro estradiol (E 2 ) and/or medroxyprogesterone acetate (MPA) treatment of Ishikawa cells and endometrial stromal cells (ESCs), PakI protein was analyzed utilizing western blot analysis and immunocytochemistry. Immunohistochemistry was performed to evaluate PakI immunoreactivity semiquantitatively in women with endometriosis and in controls. To assess the role of PakI on endometrial cell viability, crystal violet assay was performed following transfection of Ishikawa cells with PakI small interfering RNA (siRNA). RESULTS: In vitro treatment with E 2 plus MPA or MPA alone led to a significant decrease of PakI protein in Ishikawa cells and ESCs (both P < 0.05 versus control). Immunohistochemistry also revealed that PakI protein is significantly decreased during the secretory phase in both epithelial and stromal cells in the control subjects (P < 0.001 and P < 0.01, respectively). The immunoreactivity of PakI in glandular cells was significantly increased in the eutopic endometrium of women with endometriosis compared with the controls during the secretory phase (P < 0.01). Crystal violet assay has shown that transfection of Ishikawa cells with PakI siRNA led to a significant decrease of cellular viability (P < 0.05). CONCLUSIONS: These findings suggest that PakI is down-regulated by progesterone during the secretory phase in normal endometrium and increased PakI activity during the secretory phase might lead to establishment of endometriosis.

Angiogenin, a potent inducer of angiogenesis, is expressed in human endometrium. This study was performed to compare the expression of angiogenin mRNA level in the eutopic endometrium from women with and without endometriosis. Thirty-two women with advanced stage endometriosis and 29 control women were recruited. Following isolation of total RNA from endometrial tissue and reverse transcription, cDNA samples were amplified by real time polymerase chain reaction to quantify the expression of angiogenin genes. In selected patients, immunohistochemical staining was utilized to localize the area of angiogenin expression. Angiogenin mRNA level was significantly lower in the endometriosis group than in the control group during the secretory phase, especially the mid-secretory phase, and the decline was observed mainly in the women who presented with infertility. Within the endometriosis group, angiogenin mRNA levels did not differ between the proliferative and secretory phases, but, in the control group, the level in the secretory phase was higher than that during the proliferative phase. Immunohistochemistry showed that the glandular epithelial cell layer was decorated positively in both groups. These findings suggest that the relative deficiency of angiogenin expression in the secretory endometrium could impair implantation in women with advanced stage endometriosis.

In this retrospective cohort study, the effect of endometrial polypectomy carried out on the day of oocyte retrieval and on the first day of ovarian stimulation in patients with a large (≥10 mm) endometrial polyp undergoing IVF and intractyoplasmic sperm injection (ICSI) was investigated and compared. A total of 74 eligible IVF-ICSI cycles in 74 women who underwent endometrial polypectomy on either the day of oocyte pick-up (late polypectomy group, 39 cycles) or the first day of ovarian stimulation (early polypectomy group, 35 cycles) between January 2007 and July 2012 were included in this study. Patient characteristics between early and late polypectomy groups were similar. Total dose and days of recombinant human FSH administered, numbers of retrieved oocytes, mature oocytes, fertilized oocytes, grade 1 or 2 embryos and embryos transferred between the two groups were also similar, as was clinical pregnancy rate per cycle, embryo implantation rate and spontaneous abortion rate between the two groups. Therefore, endometrial polypectomy on the day of oocyte retrieval could be a more patient-friendly option for patients with a large endometrial polyp undergoing IVF-ICSI.

Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated.We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis.For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses.The study was conducted at an academic center.The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis.In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls.These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.

Twin pregnancy consisting of complete hydatidiform mole (H-mole) and a coexisting fetus occurs with an estimated incidence of 1 per 22,000–100,000 pregnancies. The incidence of this unusual twin pregnancy with complete H-mole and a coexisting fetus after in vitro fertilization and embryo transfer (IVF–ET) is not thought to be greater than that of general population. We present an unusual twin pregnancy with complete H-mole and a coexisting fetus that occurred following IVF–ET, which was terminated at 21 weeks of gestation and developed into nonmetastatic gestational trophoblastic tumor.

We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.

Objective To investigate the expression of p21-activated kinase 4 (Pak4) in both adenomyotic foci and the eutopic endometrium of women with adenomyosis, and whether the activities of matrix metalloproteinases (MMPs)-2 and -9 are regulated by Pak4 in endometrial cells. Design Experimental study using human samples and cell lines. Setting University hospital. Patient(s) Thirty-nine patients with histologic evidence of adenomyosis, and 34 patients with carcinoma in situ of the uterine cervix without adenomyosis or endometriosis. Intervention(s) Immunohistochemistry, zymography after transfection with Pak4 small interfering RNA (siRNA), and western blot analyses after nuclear factor kappa-B (NF-кB) inhibitor treatment. Main Outcome Measure(s) The Pak4 immunoreactivity of women with vs. without adenomyosis was compared semiquantitatively. The activities of MMP-2 and -9 were analyzed in eutopic endometrial stromal cells and Ishikawa cells after transfection with Pak4 siRNA. The Pak4 expression was evaluated in endometrial cells after treatment with NF-кB inhibitor. Result(s) Pak4 immunoreactivity was increased in adenomyotic foci and in the eutopic endometrium of women with adenomyosis. Transfection of endometrial cells with Pak4 siRNA led to significant decreases of MMP-2 and -9 activities. In vitro treatment of endometrial cells with tumor necrosis factor-alpha caused a significant increase of NF-кB activation and Pak4 expression, which was obviously decreased by the NF-кB inhibitor pyrrolidinedithiocarbamate. Conclusion(s) Our results suggest that Pak4 is regulated by NF-кB and that increased Pak4 expression can lead to development of adenomyosis by enhancing the invasiveness of endometrial cells through regulation of MMP-2 and -9 activities.

It has been known that most cases of ovarian hyperstimulation syndrome (OHSS) are associated with the use of exogenous gonadotropins to induce multiple ovulation. However, OHSS is infrequently associated with a spontaneous ovulatory cycle, usually in the case of multiple gestations, hypothyroidism, or polycystic ovarian syndrome. We report a case of severe OHSS in a spontaneously pregnant woman with no underlying disease.

Objective: To investigate the effect of pyridostigmine, an acetylcholinesterase inhibitor, as cotreatment for controlled ovarian hyperstimulation (COH) in low responders. Design: Randomized, double-blind, placebo-controlled study. Setting: A reproductive medicine unit in a university hospital. Patient(s): Seventy infertile women with a history of low ovarian response to COH using a GnRH agonist as part of a long stimulation protocol in previous IVF-ET cycles. Intervention(s): Sixty milligrams of pyridostigmine or placebo was administered orally twice daily from the first day of COH until the day of hCG injection in patients undergoing IVF-ET cycles. Main Outcome Measure(s): In vitro fertilization results, pregnancy outcome, and serum and intrafollicular concentrations of GH and insulin-like growth factor-1. Result(s): Pyridostigmine cotreatment was associated with significant decreases in the amount of gonadotropins and the duration of stimulation required. The clinical pregnancy rate was higher in the pyridostigmine group, but this difference was not statistically significant (25.7% vs. 11.4%). The serum GH level on the day of hCG injection was significantly higher in the pyridostigmine group than in the placebo group. Follicular fluid concentrations of GH and insulin-like growth factor-1 were significantly higher in the pyridostigmine group. Conclusion(s): This study suggests that pyridostigmine cotreatment for COH could affect the serum and intrafollicular GH and insulin-like growth factor-1 concentrations and, hence, improve the ovarian response to COH and the results of IVF in low responders undergoing IVF-ET.

It is well known that excessive thyroid hormone in the body is associated with bone loss. However, the mechanism by which thyroid hormone affects bone turnover remains unclear. It has been shown that it stimulates osteoclastic bone resorption indirectly via unknown mediators secreted by osteoblasts. To determine if interleukin-6 (IL-6) or interleukin-11 (IL-11) could be the mediator(s) of thyroid hormone-induced bone loss, we studied the effects of 3,5,3'-tri-iodothyronine (T3) on basal and interleukin-1 (IL-1)-stimulated IL-6/IL-11 production in primary cultured human bone marrow stromal cells. T3 at 10(-12)-10(-8) M concentration significantly increased basal IL-6 production in a dose-dependent manner. It also had an additive effect on IL-1-stimulated IL-6 production, but failed to elicit a detectable effect on basal or IL-1-stimulated IL-11 production. Treatment with 17beta-estradiol (10(-8) M) did not affect the action of T3 on IL-6/IL-11 production. These results suggest that thyroid hormone may stimulate bone resorption by increasing basal and IL-1-induced IL-6 production from osteoblast-lineage cells, and these effects are independent of estrogen status.

Endometriosis is a common gynecological condition characterized by enhanced proliferation, adhesiveness, invasiveness, and survival of endometrial cells after retrograde menstruation. Originally identified as a cytoskeletal regulatory kinase, p21-activated kinase 4 (Pak4) regulates diverse cellular activities that might be altered in the establishment and progression of endometriosis.The aim was to evaluate the effects of sex steroids and proinflammatory cytokines on the Pak4 expression in endometrial cells along with the functional change caused by inhibition of Pak4 expression as well as to see whether the Pak4 expression is altered in endometriosis.Pak4 expression was analyzed using immunohistochemistry and Western blot analysis. Viability and invasiveness were assayed after transfection of endometrial cells with Pak4 small interfering RNA.The Pak4 expression was significantly decreased in the stromal cells during the secretory phase as well as by in vitro treatment with progesterone. The immunoreactivity of Pak4 was significantly increased in the eutopic endometrium as well as in the ovarian endometriotic cyst of women with endometriosis compared with the control subjects. TNF-α induced a significant increase in the Pak4 expression in endometrial cells in vitro, whereas IL-1β had no effects. Transfection of endometrial cells with Pak4 small interfering RNA led to a significant decrease in viability and invasiveness in endometrial cells.These findings suggest that Pak4 is regulated by progesterone and TNF-α in endometrial cells and that the increased expression of Pak4 might lead to the establishment and progression of endometriosis by enhanced cellular viability and invasiveness in endometrial cells.

The desired objective of controlled ovarian stimulation (COS) is to allow the growth of a cohort of follicles and to facilitate the recovery of a large number of fertilizable oocytes. However, poor responders with low ovarian reserve often fail to respond adequately despite the maximal dose of gonadotropins administered, with the results that the number as well as quality of oocytes harvested may be very low. These results lead to a significant decrease of pregnancy rate in IVF cycles. Therefore, successful COS for poor responders continues to be a major challenge in IVF program. In this review, I will describe strategies for improvement of ovarian response to COS in poor responders. The strategies described may provide a means of augmenting follicular recruitment by endocrinological manipulation for poor responders undergoing IVF.

�Objective: To evaluate the effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase (MDP-EL) in comparison with standard GnRH agonist luteal long protocol (LP) in each non-obese and obese polycystic ovary syndrome (PCOS) women undergoing IVF. Methods: Two hundred eleven infertile women with PCOS were recruited and randomized to undergo either GnRH antagonist MDP-EL (antagonist group) or standard GnRH agonist luteal LP (agonist group). IVF cycle outcomes were compared between the two groups. Results: Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the antago nist group than in the agonist group. Incidence of severe ovarian hyperstimulation syndrome was significantly lower in the antagonist group. However, IVF and pregnancy outcomes were similar in the two groups. When all subjects were divided into non-obese and obese subgroups, in non-obese PCOS subgroup, IVF and pregnancy outcomes were comparable in the antagonist and agonist groups but total dose and days of rhFSH were also significantly fewer in the antagonist group. Similar findings were also observed in obese PCOS subgroup. Conclusion: GnRH antagonist MDP-EL is at least as effective as GnRH agonist LP and may be a more patient-friendly alternative in controlled ovarian stimulation for PCOS patients undergoing IVF, independent of body mass index.

We evaluated whether the proinflammatory cytokines can regulate p21-activated kinase (Pak1) expression in endometrial cells as well as whether its expression is increased in endometriotic cysts. We found that interleukin-1β up-regulates Pak1 expression in endometrial stromal cells (ESC) and that the immunoreactivity of Pak1 is increased in the endometriotic cysts.

BACKGROUND: Myolysis is one of the procedures that is claimed to provide significant improvement in myoma status without hysterectomy. Myolysis procedures have been generally performed via laparoscopy, and there are limited data on transvaginal radiofrequency (RF) myolysis. This study investigated the feasibility, efficacy and safety of transvaginal ultrasound-guided RF myolysis. METHODS: Transvaginal ultrasound-guided RF myolysis was performed on 69 premenopausal women with symptomatic uterine myomas as an outpatient procedure. Outcomes were assessed I, 3, 6 and I2 months after RF myolysis. Myoma volumes were measured by ulrasonography. Menorrhagia was evaluated by the number of soaked normal-sized sanitary products used per menstrual period and overall symptoms were evaluated using the symptom severity subscale of the uterine fibroids symptom questionnaire. RESULTS: Mean (± SD) age of patients was 39.8 ± 6.5 years. Mean baseline volume of the dominant myomas was 304.6 ± 229.I cm3 and its volume at 3 months following RF myolysis decreased compared with the previous examination (P = 0.002). An improvement of menorrhagia occurred I 3, 6 and I2 months after operation (all P < 0.00I versus baseline). Overall symptoms at I, 3, 6 and I2 months after RF myolysis also improved (all P < 0.00I versus baseline). No major complications were observed or reported. After I2 months, three patients had successfully conceived and delivered and there were no complications during labor or delivery. CONCLUSIONS: Transvaginal ultrasound-guided RF myolysis might be a safe, effective and minimally invasive outpatient procedure for uterine myoma in terms of size reduction, symptom improvement and safety.

Based on the findings of several reports that have shown an increased plasma level of di-(2-ethylhexyl) phthalate (DEHP) in women with endometriosis, the present study was designed to evaluate whether in vitro treatment with DEHP can increase viability of endometrial cells. Utilizing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay, fluorescent activated cell sorter analysis, and microscopic evaluation after Hoechst staining, we revealed that in vitro treatment with DEHP leads to increased viability of Ishikawa cells as well as endometrial stromal cells in serum-free condition and following exposure to hydrogen peroxide, which suggests that exposure to phthalate might play a role in the establishment of endometriosis.

The present study was designed to evaluate whether the expression of p21-activated kinase 1 (Pak1), which recently has been shown to be increased in the eutopic endometrium of women with endometriosis, is also increased in adenomyotic nodules as well as in the eutopic endometrium in women with adenomyosis. Comparative immunohistochemical study using a monoclonal antihuman Pak1 antibody revealed that the expression of Pak1 is increased in the eutopic endometrium of women with adenomyosis during the secretory phase, along with its increased expression in adenomyotic nodules, suggesting a possible role of Pak1 in the establishment of adenomyosis.

This prospective randomized study was performed to investigate the effectiveness of minimal stimulation using recombinant human FSH (rhFSH) and GnRH antagonist compared with GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection. Our study demonstrated that minimal stimulation in natural cycles provides similar pregnancy rates to the GnRH antagonist MDP with fewer dose and days of rhFSH used and thus can be a cost-effective alternative as a last chance before oocyte donation in low responders.

This prospective randomized study was performed to compare the efficacy of GnRH antagonist multiple-dose protocol (MDP) with or without oral contraceptive pill (OCP) pretreatment and GnRH agonist low-dose long protocol (LP) in 82 patients undergoing IVF/intracytoplasmic sperm injection (ICSI). GnRH antagonist MDP with OCP pretreatment was at least as effective as GnRH agonist low-dose LP in low responders, and can benefit the low responders by reducing the amount of FSH and the number of days of stimulation required for follicular maturation.

Objective To investigate the effects of pioglitazone on ovarian stimulation, in vitro fertilization (IVF) outcome, and intraovarian stromal blood flow in patients with polycystic ovary syndrome (PCOS). Design Prospective, randomized, controlled trial. Setting University-affiliated infertility clinic. Patient(s) Sixty infertile patients with PCOS resistant to clomiphene citrate. Intervention(s) An IVF protocol involving use of a gonadotropin-releasing hormone (GnRH) antagonist and oral contraceptive pretreatment. Patients were randomized into two groups: pioglitazone (30 mg daily) in the study group or placebo in the control group, commenced on the day on which oral contraceptive intake began. Main Outcome Measure(s) Ovarian stimulation, IVF outcome, and resistance index of the intraovarian stromal artery. Result(s) The resistance index value on the day of human chorionic gonadotropin (hCG) injection in the study group was statistically significantly higher in the study group than in controls. The serum estradiol level and number of retrieved oocytes were statistically significantly lower in women treated with pioglitazone. However, the number of mature oocytes and fertilized oocytes, and the clinical pregnancy rate were similar in both groups. Conclusion(s) Pioglitazone therapy reduced intraovarian stromal blood flow and might be beneficial in improving both the response to ovarian stimulation and IVF outcome in PCOS patients.

Objective Nuclear factor kappa-B (NF-κB) is a critical proinflammatory regulator that has been suggested to play a pivotal role in the pathogenesis and pathophysiology of endometriosis. In the present study, we aimed to evaluate whether the expression of NF-κB p65 subunit is increased in the eutopic endometrium and/or in the adenomyosis nodule of women with adenomyosis. Methods Thirty-three women with histologically confirmed adenomyosis after laparoscopic or transabdominal hysterectomy were recruited. Women with carcinoma in situ of uterine cervix without evidence of adenomyosis or endometriosis (n=32) served as controls. Formalin-fixed, paraffin-embedded archival tissues were sectioned and immunostained utilizing a monoclonal anti-human NF-κB p65 subunit antibody, and the immunoreactivity of NF-κB p65 subunit was compared between women with and without adenomyosis. Results The immunoreactivities of both the nuclear and the cytoplasmic NF-κB p65 subunit were significantly increased in the stromal cells in the eutopic endometrium as well as in the adenomyosis nodule of women with adenomyosis compared with controls, respectively. The nuclear expression of NF-κB p65 subunit was significantly higher in the glandular cells in the eutopic endometrium as well as the adenomyosis nodule of women with adenomyosis compared with controls, respectively. Conclusion The expression of NF-κB p65 is increased in the eutopic endometrium and adenomyosis nodule of women with adenomyosis, which strongly suggest that NF-κB plays a critical role in the pathogenesis and/or pathophysiology of adenomyosis.

Human embryonic stem cells (hESCs) are pluripotent, whereby they can proliferate endlessly and differentiate into many different cell types. At the molecular level, little is known of the mechanisms underlying their capability for self-renewal and differentiation. In the present study, we established two new hESC lines (AMC-hES1 and AMC-hES2) and demonstrated the existence of a regulator that may be a key molecule in hESC dynamics. Spa-1 is a principal Ras-proximate 1 (Rap1) GTPase-activating protein in hematopoietic progenitor cells that regulates Rap1-related signal transduction and is expressed restrictively in human adult tissues (bone marrow, thymus, and spleen). To investigate its functions in hESCs, we examined spa-1 expression profiles during hESC differentiation and used RNA interference (RNAi) to downregulate spa-1 in these cells. Our results show that Spa-1 is expressed in undifferentiated hESCs and is downregulated during hESC differentiation. In addition, the process of passing from the mode of self-renewal to that of differentiation in hESCs was regulated by spa-1 via Rap1/Raf/mitogen-activated protein kinase kinase/extracellular signal-related kinase signaling. An RNAi expression vector against spa-1 (pSUPER.retro.puro) was transfected into hESCs, which were seen to differentiate into three germ layers in spite of being in the undifferentiated condition. Based on our findings, therefore, it appears that spa-1 may be involved in hESC dynamics, and our results provide fundamental information regarding the self-renewal and differentiation of hESCs.