Social determinants of health that impact the time to diagnosis and treatment of infertility in Taiwan.

BACKGROUND/PURPOSE: Taiwan is one of the countries with the lowest birth rate in the world. We investigated factors associated with the time to diagnosis and treatment of infertility in Taiwan. METHODS: The study was conducted through an online questionnaire in December 2021. The questionnaire was adapted from a previously published multinational survey, and culture-specific questions were added. 91 infertile patients and 89 partners of patients in Taiwan, aged 20- to 45- year-old, were included. RESULTS: The average duration before diagnosis was 2.9 years, followed by 1.5 years before treatment. Older age at marriage (p = 0.0024), higher education level (P = 0.0001), and a higher gender equality score (p = 0.0031) were associated with earlier diagnosis. Conversely, folk therapy use was linked to later diagnosis (p < 0.0001) and treatment (p < 0.0001). Notably, in the female (p = 0.039) and patient (p = 0.0377) subgroups, a higher gender equality score was associated with a shorter duration of folk therapy. Subjectively, the most frequent factor influencing treatment decision was affordability or lack thereof. The government subsidy for in vitro fertilization led to increased treatment willingness for 46.3% of respondents, and 47.3% reported more likely to pursue earlier treatment. CONCLUSIONS: This study highlights the influence of education, gender equality, folk therapy, and government subsidy on fertility care decisions. To improve the timeliness of infertility healthcare in Taiwan, potential strategies include promoting education, fostering gender equality, providing financial support, and raising awareness on the association between folk therapy and delayed medical care.

Design, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitors.

Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin-based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM-1min-1 on human placenta STS, respectively.

Progestin-primed ovarian stimulation versus GnRH antagonist protocol in poor responders: Risk of premature LH surge and outcome of oocyte retrieval.

PURPOSE: For poor ovarian responders (PORs), gonadotropin-releasing hormone (GnRH) antagonist was commonly used for prevention of premature LH surge during controlled ovarian stimulation (COS) over the past two decades. The application of progestin-primed ovarian stimulation (PPOS) recently increased, but the role of PPOS for PORs was uncertain. We aimed to analyze the incidence of premature luteinizing hormone (LH) surge and the outcome of oocyte retrieval among PPOS and GnRH antagonist protocol for PORs. METHODS: This was a single-center retrospective study, which enrolled the PORs (defined by the Bologna criteria) undergoing COS with PPOS or flexible GnRH antagonist protocol during January 2018 to December 2021. We compared the incidence of premature LH surge (LH > 10 mIU/mL) and the outcome of oocyte retrieval between the PPOS group and the GnRH antagonist group. RESULTS: A total of 314 women were recruited, with 54 in the PPOS group and 260 in the GnRH antagonist group. The PPOS group had lower incidence of premature LH surges compared with the GnRH antagonist protocol group (5.6% vs 16.9%, P value 0.035). There was no significant difference between the two groups regarding the number of oocytes retrieved (3.4 vs 3.8, P value 0.066) and oocyte retrieval rates (88.9% vs 88.0%, P value 0.711). CONCLUSION: Compared with PPOS, GnRH antagonist protocol had higher risk of premature LH surges for PORs but may not affect pregnancy rates. PPOS is suitable for oocyte or embryo cryopreservation, but should not totally replace GnRH antagonist protocol for patients undergoing in vitro fertilization (IVF).

Usage and cost-effectiveness of elective oocyte freezing: a retrospective observational study.

BACKGROUND: The previous model-based cost-effectiveness analyses regarding elective oocyte cryopreservation remained debatable, while the usage rate may influence the cost per live birth. The aim of this study is to disclose the usage and cost-effectiveness of the planned cryopreserved oocytes after oocyte thawing in real-world situations. METHODS: This was a retrospective single-center observational study. Women who electively cryopreserved oocytes and returned to thaw the oocytes were categorized as thawed group. The oocytes were fertilized at our center and the sperm samples for each individual was retrieved from their respective husbands. Clinical outcomes were traced and the cumulative live birth rate per thawed case was calculated. The costs from oocyte freezing cycles to oocyte thawing, and embryo transfer cycles were accordingly estimated. The cumulative cost per live birth was defined by the cumulative cost divided by the live births per thawed case. RESULTS: We recruited 645 women with 840 oocyte retrieval cycles for elective oocyte freezing from November 2002 to December 2020. The overall usage rate was 8.4% (54/645). After the storage duration exceeded ten years, the probabilities of thawing oocytes were 10.6%, 26.6%, and 12.7% from women who cryopreserved their oocytes at the age ≤ 35 years, 36-39 years, and ≥ 40 years, respectively (P = 0.304). Among women who thawed their oocytes, 31.5% (17/54) of women achieved at least one live birth. For the age groups of ≤ 35 years, 36-39 years, and ≥ 40 years, the cumulative live birth rates per thawed case were 63.6%, 42.3%, and 17.6%, respectively (P = 0.045), and the cumulative costs for one live birth were $11,704, $17,189, and $35,642, respectively (P < 0.001). CONCLUSIONS: The overall usage rate was 8.4% in our cohort. The cumulative live birth rate was greatest in the youngest group and the cumulative cost per live birth was highest in the oldest group, which was threefold greater than that in the group aged ≤ 35 years. The findings added to the limited evidence of the usage rate in real-world situations, which could hopefully aid future analysis and decision-making in public health policy and for women willing to preserve fertility. TRIAL REGISTRATION: None.

The Design, Structure-Activity, and kinetic studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates as Steroid sulfatase inhibitors.

Steroid sulfatase inhibitors block the local production of estrogenic steroids and are attractive agents for the treatment of estrogen-dependent cancers. Inspiration of coumarin-based inhibitors, we synthesized thirty-two 5-oxa-1,2,3,4-tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates, focusing on the substitution derivatives on the adjacent phenyl ring and evaluated their abilities to block STS from human placenta and MCF-7 cells. SAR analysis revealed that the incorporation of chlorine at either meta and/or para position of the adjacent phenyl ring of the tricyclic skeleton enhanced STS inhibition. Di-substitutions at the adjacent phenyl ring were superior to mono and tri-substitutions. Further kinetic analysis of these compounds revealed that chloride-bearing compounds, such as 19m, 19v, and 19w, had KI of 0.02 to 0.11 nM and kinact/KI ratios of 8.8-17.5 nM-1min-1, a parameter indicated for the efficiency of irreversible inhibition. We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19m, 19v, and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75-1 cell, which was a hormone-dependent cancer cell line with high STS expression.

Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy.

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.

Changes in peripheral mitochondrial DNA copy number in metformin-treated women with polycystic ovary syndrome: a longitudinal study.

BACKGROUND: Patients with polycystic ovarian syndrome (PCOS) are associated with known alterations in mitochondria DNA copy number (mtDNA-CN). The aim of this study is to study the change in mtDNA-CN in patients with PCOS who were treated with metformin. METHODS: This is a prospective cohort of patients with PCOS, who received metformin for one year. From 2009 to 2015, 88 women diagnosed with PCOS, based on the Rotterdam criteria, were enrolled. Serial measurements of mtDNA-CN, 8-hydroxydeoxyguanosine (8-OHdG), anthropometric, metabolic, endocrine, and inflammatory markers were obtained before and after 3, 6, and 12 months of treatment. RESULTS: A significant decrease in mtDNA-CN was seen over the course of one year. Other markers, including 8-OHdG, testosterone, free androgen index, blood pressure and liver enzymes, also decreased in the same interval. On regression analysis, there was a significant association between the change in mtDNA-CN and serum total testosterone, and no association between mtDNA-CN and metabolic factors. CONCLUSIONS: Treatment with metformin is associated with a time-dependent decrease in mtDNA-CN in patients with PCOS who are treated over the course of one year. This may signify a reduction in mitochondria dysfunction. The change in mtDNA-CN corresponds to a similar change in serum total testosterone, and suggests a possible relationship between mtDNA-CN and testosterone. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00172523 . Registered September 15, 2005.

Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors.

Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC50  0.13 µM) and MCF-7 cell lines (IC50 1.35 µM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with KI and kinact value of 86.9 nM and 158.7 min-1, respectively.

A novel GnRH-antagonist protocol by switching to medroxyprogesterone when patients being at risk of ovarian hyperstimulation syndrome during ovarian stimulation.

BACKGROUND/PURPOSE: To investigate whether switching GnRH antagonist (GnRHant) to medroxyprogesterone acetate (MPA) sequentially in the middle of controlled ovarian stimulation could effectively prevent premature LH surge in a GnRHant protocol in patients turn out to be at a high risk of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. METHODS: This is a retrospective cohort study. RESULTS: Premature LH surge did not occur in both groups of patients. The switch protocol group had a significantly fewer days of GnRHant treatment (3.1 ± 1.0 vs. 6.5 ± 1.2) compared with GnRHant protocol group. The mean duration of MPA treatment was 3.6 ± 1.1 days. There were no statistically significant differences in terms of live birth, implantation, and clinical pregnancy rates. CONCLUSION: This study showed that MPA could sequentially replace GnRHant and effectively prevent premature LH surge after several days of GnRHant administration in patients being at high risk of OHSS during controlled ovarian stimulation. Switch protocol could individualize freeze-all policy and reduce the injection burden of GnRHant.

Factors increasing the detection rate of intrauterine lesions on hysteroscopy in infertile women with sonographically normal uterine cavities.

BACKGROUND: Detection of intrauterine lesions is important for infertile women, as the uterine cavity is the site for embryo growth. This study aims to investigate factors that increase the detection rate of intrauterine lesions on office hysteroscopy in infertile women with sonographically normal uterine cavities. METHODS: We retrospectively enrolled 1726 infertile women who had normal uterine cavities on two-dimensional transvaginal sonography. Office hysteroscopy was performed in the early proliferative phase of the menstrual cycle. RESULTS: Intrauterine lesions were detected in 260 (15.1%) of the 1726 women. In women who suffered from abnormal uterine bleeding (AUB), hypomenorrhea or had a history of dilation and curettage (D&C), the detection rates of intrauterine lesions on office hysteroscopy were 41.4%, 22.2% and 19.4%, respectively. The predictive rate of abnormal hysteroscopic finding was 22.4% in women with at least one of these three clinical features, while it was 9.6% in those without. CONCLUSION: AUB, hypomenorrhea, and previous D&C are the three factors that increase the detection rate of intrauterine lesions on office hysteroscopy in infertile women with sonographically normal uterine cavities.

Lower rate of early pregnancy loss in patients experiencing early-onset low LH in GnRH antagonist cycles supplemented with menotropin.

BACKGROUND/PURPOSE: The role of LH during controlled ovarian stimulation (COS) in the general population remains contentious. There is no consensus on the indications for LH supplementation during COS. The purpose of this study is to determine whether menotropin supplement is associated with decreases in early pregnancy loss rates in patients exhibiting low endogenous LH during COS. METHOD: This is a single-center, retrospective cohort from a university-affiliated hospital. Patients were enrolled from the in-vitro fertilization center from January, 2011 to December, 2014. Patients who experienced a LH level â‰¦ 0.8 mIU/mL during stimulation were identified, and patients that received menotropin supplementation were compared to those without menotropin supplementation. Outcome variables, including the number of oocytes retrieved, embryos obtained, implantation rates, pregnancy rates and early pregnancy loss rates, were compared. RESULTS: Patients that experienced low LH during GnRH antagonist protocol and were supplemented with menotropin were associated with lower early pregnancy loss when compared with patients without menotropin supplementation (26.7% vs. 11.5%, p = 0.045). More specifically, in patients who exhibited early-onset low LH, before the use of GnRH antagonists, menotropin supplementation was associated with significantly lower early pregnancy loss compared with non-supplemented patients (3.3% vs. 29.0%, OR: 0.08, p = 0.012). Beneficial effects persisted after adjusting for confounders (aOR: 0.103, 95% CI: 0.011-0.933). CONCLUSION: Menotropin supplementation is associated with decreased early pregnancy loss in patient who exhibited low LH during GnRH antagonist cycles. This effect is especially prominent in patients who experience low LH before the start of GnRH antagonists.

Increased platelet factor 4 and aberrant permeability of follicular fluid in PCOS.

BACKGROUND/PURPOSE: Abnormal folliculogenesis is one of the cardinal presentations of polycystic ovarian syndrome (PCOS) and permeability of follicular wall has been proposed to be involved in the normal follicular growth. However, whether or not there is a change in intrafollicular permeability underlies PCOS is unknown. METHODS: This was a tertiary center-based case-control study. From 2014 to 2015, thirteen patients with PCOS who underwent in vitro fertilization-embryo transfer (IVF-ET) were enrolled. Eleven normo-ovulatory patients who underwent IVF-ET due to male factor and/or tubal factor infertility were enrolled as the control group. The influence of ovarian follicular fluid (FF) on endothelial cell permeability was evaluated using a human umbilical vein endothelial cell monolayer permeability assay. The intrafollicular expression profiles of angiogenesis-related proteins were analyzed using a Human Angiogenesis Protein Array Kit. RESULTS: The FF from PCOS patients caused significantly poorer endothelial cell permeability comparing with the effect of FF from the control group (46% ± 12% vs. 58% ± 9%, P = 0.023). Among the 55 angiogenesis-related proteins tested, there was a significantly higher level of intrafollicular platelet factor 4 (PF4) and PF4/IL-8 complex in the PCOS group (p = 0.004). The anti-permeability effect of PF4 was related to the decrease in the intercellular gaps and antagonistic binding with IL-8. CONCLUSION: Our study provides the first evidence of the pathophysiologic contribution of the well-known angiostatic protein, PF4, on human reproductive biology. The increase of the intrafollicular PF4 and its anti-permeability effect might affect the formation of FF and folliculogenesis in PCOS.

HSD3B1 gene polymorphism and female pattern hair loss in women with polycystic ovary syndrome.

BACKGROUND/PURPOSE: Genetic variant of HSD3B1 1245 is known to augment androgen production at peripheral tissue as skin. This study aimed to investigate whether women with polycystic ovary syndrome inheriting this variant exhibit specific androgenic phenotypes. METHODS: A cross-sectional study of Taiwanese women with polycystic ovary syndrome, defined by Rotterdam criteria, at the reproductive endocrinology outpatient clinic in a university affiliated hospital. RESULTS: The presence of female pattern hair loss in women with polycystic ovary syndrome was significantly associated with an increased body mass index, decreased sex hormone binding globulin and high density lipoprotein cholesterol levels, elevated triglyceride levels, and increased prevalence of hypertension. Using stepwise multivariate logistic regression analysis, body mass index, triglyceride and HSD3B1 1245 AC or CC genotype were significantly related to female pattern hair loss in women with polycystic ovary syndrome after considering other variables. Overweight women with polycystic ovary syndrome had significantly higher risk of female pattern hair loss than normal-weight women with polycystic ovary syndrome. The presence of female pattern hair loss was higher in overweight women with polycystic ovary syndrome who comprised HSD3B1 AC or CC genotype compared with wild type. CONCLUSION: Carrying the HSD3B1 1245C allele and overweight are associated with the presence of female pattern hair loss in women with polycystic ovary syndrome.

Effect of iron overload on impaired fertility in male patients with transfusion-dependent beta-thalassemia.

BackgroundTo investigate the fertility of male patients with transfusion-dependent beta-thalassemia, and to use magnetic resonance imaging (MRI) as a novel method to assess the iron overload status of testis in such patients.MethodsTwenty-one male patients with transfusion-dependent beta-thalassemia and five normal male controls enrolled in this study. Hormonal profiles, iron levels, MRI testicular dimension, MRI T2 values, parameters for sperm quality, and sperm DNA fragmentation (SDF) of participants were measured.ResultsThe MRI T2 values of the testis were significantly lower in transfusion-dependent beta-thalassemia patients than in normal controls (P=0.027), and they correlated to serum ferritin levels in all enrolled subjects (R2=0.258, P=0.008). There were significantly lower sperm concentrations (P=0.037), a lower percentage of sperm with normal morphology (P=0.001), and a higher percentage of SDF (P=0.009) in transfusion-dependent beta-thalassemia patients without hypogonadotropic hypogonadism and with spontaneous spermatogenesis compared with normal controls. The percentage of SDF was significantly correlated with serum ferritin levels in transfusion-dependent beta-thalassemia male patients with spontaneous spermatogenesis (R2=0.48, P=0.009).ConclusionOur study is the first demonstration of iron deposition in the testis of patients with transfusion-dependent beta-thalassemia based on imaging, and such findings might explain the high prevalence of impaired fertility in above patients with normal pituitary function.

Advantages of cumulative pregnancy outcomes in freeze-all strategy in high responders - A case-control matching analysis of a large cohort.

BACKGROUND/PURPOSE: The freeze-all strategy in high responders is considered to be a safe and effective strategy for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment; however, the cumulative pregnancy outcomes have not been established. METHODS: A retrospective, single-center cohort study was conducted and 1311 high-responder patients (>20 oocytes retrieved and/or a serum estradiol level > 3000 pg/ml on the triggering day) were recruited from 2006 to 2015. The study group (n = 351) underwent the freeze-all strategy with subsequent thawed embryo transfer (ET), and the control group (n = 960) received fresh-cycle ET and subsequent thawed ET if needed. A case-control matching analysis was performed to match the two groups for the number of retrieved oocytes. The primary outcomes were the ongoing pregnancy rate (OPR) of the first ET cycle and the cumulative OPR. RESULTS: After matching, there was a significantly higher OPR in the first ET cycle (49.5% vs. 32.2%, p < 0.0001; n = 301 in each group) and the cumulative OPR (69.4% vs. 55.1%, p < 0.0001) in the study group, with significantly fewer total transferred embryos and cycles. The advantages of the freeze-all strategy for the OPR in the first ET cycle (OR: 1.97, p < 0.0001) and the cumulative OPR (OR: 1.49, p = 0.032) remained statistically significant after adjusting for other possible confounding factors in multivariate logistic regression analysis. CONCLUSION: For high responders, the freeze-all strategy with thawed ET achieved a significantly higher OPR in the first ET cycle and a higher cumulative OPR than the fresh ET strategy.

Iron suppresses ovarian granulosa cell proliferation and arrests cell cycle through regulating p38 mitogen-activated protein kinase/p53/p21 pathway.

Iron is an essential nutrient that may exert toxic effects when it accumulates in tissues. Little is known regarding its effects on gonadal function. Both Fe2+ and Fe3+ could be released from iron deposition. We employed mouse nonluteinized granulosa cell for in vitro studies and human ovarian tissues for Prussian blue and immunohistochemical staining to identify the iron deposition and effect in vivo. After treatment with FeSO4-7H2O or FeCl3 in granulosa cell cultured with follicle-stimulating hormone (FSH) for 48 h, we found that Fe2+ significantly suppressed FSH-induced granulosa cell proliferation and arrested the cell cycle at the G2/M phase by cell proliferation assay and flow cytometry. Fe2+ significantly increased intracellular reactive oxygen species (ROS) and ferritin levels of mouse granulosa cells. The increases in p21 and p53 messenger RNA and protein expression facilitated by Fe2+ treatment in mouse granulosa cells were significantly suppressed by separate treatments with p53 small interfering RNA and p38 mitogen-activated protein kinase (MAPK) inhibitors. An ROS inhibitor downregulated Fe2+-induced increases in p38MAPK expression in mouse granulosa cells. Quantitative analysis of immunohistochemical staining revealed that human ovarian tissue sections with positive Prussian blue staining had lower levels of proliferating cell nuclear antigen expression, but higher levels of p21, p53, and CDC25C expression than those with negative Prussian blue staining. Conclusively, Fe2+ could directly arrest the cell cycle and inhibit granulosa cell proliferation by regulating the ROS-mediated p38MAPK/p53/p21 pathway. Therefore, iron can directly affect female gonadal function.

Management of endometrial polyps incidentally diagnosed during IVF: a case-control study.

An endometrial polyp is a frequently encountered abnormality of the uterine cavity that may interfere with normal embryo implantation. In this case-control study, we enrolled 56 women in whom endometrial polyps were incidentally diagnosed by transvaginal ultrasound and office hysteroscopy during IVF (Group 1), and 112 age-matched IVF controls randomly selected from the same time period (group 2). Cryopreserved embryos were transferred in group 1 whereas fresh embryos were transferred in group 2, which is a limitation of the study. Hysteroscopic polypectomy was carried out for those in group 1, followed by vitrified-warmed embryo transfer 1-7 months later. Results revealed that the clinical pregnancy rate was higher in group 1 than in group 2 (63% versus 41%, P = 0.009), but the embryo implantation rates were not different between the two groups (26% versus 20%). In group 1, pregnancy rates (64%, 69%, and 53% respectively) and embryo implantation rates (30%, 24%, and 23%, respectively) were similar among women that received vitrified-warmed embryo transfer at 1, 2, and 3 months or over after hysteroscopic polypectomy. We conclude that, for women with endometrial polyps incidentally diagnosed during IVF, pregnancy outcomes are not compromised after hysteroscopic polypectomy followed by vitrified-warmed embryo transfer.

High Estradiol Concentrations Induce Heat Shock Protein 70 Expression and Suppress Nuclear Factor Kappa B Activation in Human Endometrial Epithelial Cells.

The high serum estradiol (E2) concentrations induced during in vitro fertilization are detrimental to endometrial receptivity and may result in lower embryo implantation rates. We have previously found that high E2 concentrations inhibit the activation of nuclear factor kappa B (NF-kappa B), which led to endometrial epithelial cells (EECs) apoptosis. The objective of this study is to investigate the signaling pathways through which high E2 results in NF-kappa B downregulation in EECs. Isolated human EECs were cultured in different concentrations of E2 (10-10, 10-9, 10-8, 10-7 M). The expression of heat shock protein 70 (Hsp70) and heat shock factor 1 (HSF-1) were upregulated under supraphysiological E2 (10-7 M) concentration, whereas phosphorylated inhibitory kappa B-alpha (pI kappa B-alpha) and NF-kappa B p65 subunits were downregulated. Immunohistochemistry of C57BL/6 mouse EECs, that were exposed in vivo to high serum E2 from the administration of 20 IUs of equine chorionic gonadotropin, also demonstrated the same increase in HSF-1 and Hsp70 expression, and decrease in NF-kappa B. Immunoprecipitation of the induced Hsp70 proteins was achieved with the addition of inhibitory kappa B kinase gamma (IKK-gamma) antibodies, and elimination of this reaction occurred after addition of hsp70 siRNA. In conclusion, high E2 concentrations enhance HSF-1 and Hsp70 expression in EECs. The induced Hsp70 forms a complex with IKK-gamma and inhibits pI kappa B-alpha, which consequently suppresses NF-kappa B activation.

Frequency of low serum LH is associated with increased early pregnancy loss in IVF/ICSI cycles.

The role of LH during ovarian stimulation remains uncertain. Previous studies defined the low LH group using a single LH measurement on a predefined day of stimulation possibly not reflecting the entire follicular phase. This study retrospectively collected data from 619 IVF/ICSI cycles with GnRH antagonist and recombinant FSH. The low LH group was defined as LH concentration ≤0.8 mIU/ml at any time during the cycle. Pregnancy results were compared between patients with one episode of low LH or more than two episodes of low LH (study group) and those without low LH (control group). There was no difference in fertilization rates between the two groups (67.5 ± 1.7% versus 68.8 ± 1.0%, respectively). The implantation rates (20.4% versus 25.2%), clinical pregnancy rates (43.9% versus 45.2%) and live-birth rates (LBR) (23.7% versus 30.4%) appeared lower in the study group, but the differences were not significant. In the study group, there were significantly increased early pregnancy loss rates (31.1% versus 16.3%, P = 0.012). The odds of early pregnancy loss increases by 1.55 fold for increased episodes of low serum LH (P = 0.029). Whether the adverse outcome is due to impaired oocyte quality or an endometrial component deserves further investigation.