Finding of the optimal preparation and timing of endometrium in frozen-thawed embryo transfer: a literature review of clinical evidence.

Frozen-thawed embryo transfer (FET) has been a viable alternative to fresh embryo transfer in recent years because of the improvement in vitrification methods. Laboratory-based studies indicate that complex molecular and morphological changes in endometrium during the window of implantation after exogenous hormones with controlled ovarian stimulation may alter the interaction between the embryo and endometrium, leading to a decreased implantation potential. Based on the results obtained from randomized controlled studies, increased pregnancy rates and better perinatal outcomes have been reported following FET. Compared to fresh embryo transfer, fewer preterm deliveries, and reduced incidence of ovarian hyperstimulation syndrome were found after FETs, yet there is a trend of increased pregnancy-related hypertensive diseases in women receiving FET. Despite the increased application of FET, the search for the most optimal priming protocol for the endometrium is still undergoing. Three available FET protocols have been proposed to prepare the endometrium: i) natural cycle (true natural cycle and modified natural cycle) ii) artificial cycle (AC) or hormone replacement treatment cycle iii) mild ovarian stimulation (mild-OS) cycle. Emerging evidence suggests that the optimal timing for FET using warmed blastocyst transfer is the LH surge+6 day, hCG administration+7 day, and the progesterone administration+6 day in the true natural cycle, modified natural cycle, and AC protocol, respectively. Although still controversial, better clinical pregnancy rates and live birth rates have been reported using the natural cycle (true natural cycle/modified natural cycle) compared with the AC protocol. Additionally, a higher early pregnancy loss rate and an increased incidence of gestational hypertension have been found in FETs using the AC protocol because of the lack of a corpus luteum. Although the common clinical practice is to employ luteal phase support (LPS) in natural cycles and mild-OS cycles for FET, the requirement for LPS in these protocols remains equivocal. Recent findings obtained from RCTs do not support the routine application of endometrial receptivity testing to optimize the timing of FET. More RCTs with rigorous methodology are needed to compare different protocols to prime the endometrium for FET, focusing not only on live birth rate, but also on maternal, obstetrical, and neonatal outcomes.

Establishment of the fetal-maternal interface: developmental events in human implantation and placentation.

Early pregnancy is a complex and well-orchestrated differentiation process that involves all the cellular elements of the fetal-maternal interface. Aberrant trophoblast-decidual interactions can lead to miscarriage and disorders that occur later in pregnancy, including preeclampsia, intrauterine fetal growth restriction, and preterm labor. A great deal of research on the regulation of implantation and placentation has been performed in a wide range of species. However, there is significant species variation regarding trophoblast differentiation as well as decidual-specific gene expression and regulation. Most of the relevant information has been obtained from studies using mouse models. A comprehensive understanding of the physiology and pathology of human implantation and placentation has only recently been obtained because of emerging advanced technologies. With the derivation of human trophoblast stem cells, 3D-organoid cultures, and single-cell analyses of differentiated cells, cell type-specific transcript profiles and functions were generated, and each exhibited a unique signature. Additionally, through integrative transcriptomic information, researchers can uncover the cellular dysfunction of embryonic and placental cells in peri-implantation embryos and the early pathological placenta. In fact, the clinical utility of fetal-maternal cellular trafficking has been applied for the noninvasive prenatal diagnosis of aneuploidies and the prediction of pregnancy complications. Furthermore, recent studies have proposed a viable path toward the development of therapeutic strategies targeting placenta-enriched molecules for placental dysfunction and diseases.

Growth hormone in fertility and infertility: Mechanisms of action and clinical applications.

Secreted by the anterior pituitary gland, growth hormone (GH) is a peptide that plays a critical role in regulating cell growth, development, and metabolism in multiple targeted tissues. Studies have shown that GH and its functional receptor are also expressed in the female reproductive system, including the ovaries and uterus. The experimental data suggest putative roles for GH and insulin-like growth factor 1 (IGF-1, induced by GH activity) signaling in the direct control of multiple reproductive functions, including activation of primordial follicles, folliculogenesis, ovarian steroidogenesis, oocyte maturation, and embryo implantation. In addition, GH enhances granulosa cell responsiveness to gonadotropin by upregulating the expression of gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), indicating crosstalk between this ovarian regulator and the endocrine signaling system. Notably, natural gene mutation of GH and the age-related decline in GH levels may have a detrimental effect on female reproductive function, leading to several reproductive pathologies, such as diminished ovarian reserve, poor ovarian response during assisted reproductive technology (ART), and implantation failure. Association studies using clinical samples showed that mature GH peptide is present in human follicular fluid, and the concentration of GH in this fluid is positively correlated with oocyte quality and the subsequent embryo morphology and cleavage rate. Furthermore, the results obtained from animal experiments and human samples indicate that supplementation with GH in the in vitro culture system increases steroid hormone production, prevents cell apoptosis, and enhances oocyte maturation and embryo quality. The uterine endometrium is another GH target site, as GH promotes endometrial receptivity and pregnancy by facilitating the implantation process, and the targeted depletion of GH receptors in mice results in fewer uterine implantation sites. Although still controversial, the administration of GH during ovarian stimulation alleviates age-related decreases in ART efficiency, including the number of oocytes retrieved, fertilization rate, embryo quality, implantation rate, pregnancy rate, and live birth rate, especially in patients with poor ovarian response and recurrent implantation failure.

Investigating the Relationships among Stressors, Stress Level, and Mental Symptoms for Infertile Patients: A Structural Equation Modeling Approach.

OBJECTIVE: Patients with infertility are a high risk group in depression and anxiety. However, an existing theoretically and empirically validated model of stressors, stress, and mental symptoms specific for infertile patients is still a void. This study aimed to determine the related factors and their relational structures that affect the level of depressive and anxiety symptoms among infertile patients. METHODS: A cross-sectional sample of 400 infertility outpatients seeking reproduction treatments in three teaching hospitals across Taiwan participated in the structured questionnaire survey in 2011. The hypothesized model comprising 10 latent variables was tested by Structural Equation Modeling using AMOS 17. RESULTS: Goodness-of-fit indexes, including χ2/DF = 1.871, PGFI = 0.746, PNFI = 0.764, and others, confirmed the modified model fit the data well. Marital stressor, importance of children, guilt-and-blame, and social stressor showed a direct effect on perceived stress. Instead of being a factor of stress, social support was directly and positively related to self-esteem. Perceived stress and self-esteem were the two major mediators for the relationships between stressors and mental symptoms. Increase in social support and self-esteem led to decrease in mental symptoms among the infertile patients. CONCLUSIONS: The relational structures were identified and named as the Stressors Stress Symptoms Model, clinically applied to predict anxiety and depression from various stressors. Assessing sources and level of infertility-related stress and implementing culturally-sensitive counseling with an emphasis on positive personal value may assist in preventing the severity of depression and anxiety.

Electroacupuncture reduces uterine artery blood flow impedance in infertile women.

OBJECTIVE: To evaluate the effects of electroacupuncture (EA) on pregnancy rate and uterine artery blood flow impedance in patients undergoing in vitro fertilization (IVF). MATERIALS AND METHODS: This prospective, randomized trial was carried out in the IVF center of China Medical University Hospital in Taiwan, from February 1, 2004 to January 30, 2005. A total of 44 patients were enrolled in the study. Of these, 30 were allocated to acupuncture, and 14 were allocated to no acupuncture. EA was performed four times, twice a week for 2 weeks, from day 2 of the study to the day before oocyte retrieval. After patients felt the needle reaction, the needles were attached to an electrical stimulator for 30 minutes. Clinical pregnancy and pulsatility index (PI) of right and left uterine arteries before and after EA were measured. RESULTS: There was no significant difference in pregnancy rate between the two groups (acupuncture group, 30%; non-acupuncture group, 28.6%). The mean PI of both uterine arteries was significantly reduced after EA (left uterine artery, 2.3 to 2.0; right uterine artery, 2.4 to 2.2). There was no significant change in PI in the group with no acupuncture (left uterine artery, 2.5 to 2.3; right uterine artery, 2.4 to 2.3). CONCLUSION: EA could be useful for reducing uterine artery blood flow impedance, but did not increase the pregnancy rate in patients undergoing IVF.

Hispolon from Phellinus linteus has antiproliferative effects via MDM2-recruited ERK1/2 activity in breast and bladder cancer cells.

The MDM2 proto-oncogene is overexpressed in many human tumors. Although MDM2 inhibits tumor-suppressor function of p53, there exists a p53-independent role for MDM2 in tumorigenesis. Therefore, downregulation of MDM2 has been considered an attractive therapeutic strategy. Hispolon extracted from Phellinus species was found to induce epidermoid and gastric cancer cell apoptosis. However, the mechanisms are not fully understood. Herein, we report our findings that hispolon inhibited breast and bladder cancer cell growth, regardless of p53 status. Furthermore, p21(WAF1), a cyclin-dependent kinase inhibitor, was elevated in hispolon-treated cells. MDM2, a negative regulator of p21(WAF1), was ubiquitinated and degraded after hispolon treatment. We also found that activated ERK1/2 (extracellular signal-regulated kinase1/2) was recruited to MDM2 and involved in mediating MDM2 ubiquitination. Based on this finding, we investigated whether the sensitivity of cells to hispolon was related to ERK1/2 activity. The results indicated that cells with higher ERK1/2 activity were more sensitive to hispolon. In addition, hispolon-induced caspase-7 cleavage was inhibited by the ERK1/2 inhibitor, U0126. In conclusion, hispolon ubiquitinates and downregulates MDM2 via MDM2-recruited activated ERK1/2. Therefore, hispolon may be a potential anti-tumor agent in breast and bladder cancers.

One-year soy isoflavone supplementation prevents early postmenopausal bone loss but without a dose-dependent effect.

It is believed that soy isoflavone has much potential effectiveness on the postmenopausal status; however, the optimal dose for preventing postmenopausal bone loss still remains unclear. This open-labeled, self-controlled pilot study was undertaken to determine the effect of 1-year supplementation of different high dosages of soy isoflavone in postmenopausal Taiwanese women. Forty-three women aged 45-67 years were enrolled and randomly assigned into a control (C), 100 mg/day isoflavone (IF100) and 200 mg/day isoflavone (IF200) groups for 1 year. Dual-energy X-ray absorptiometry and other related biochemical markers of bone metabolism were measured. Results indicated that the decrease in bone mineral density (BMD) was significant for lumbar vertebrae L1-3, L1-4 and the femur neck in the C group; surprisingly, the BMD of L1-3 was significantly elevated in the IF100 group; however, there were no consistent responses in the IF200 group. No significant change except loss of the bone mineral content of Ward's triangle (P=.003) was found in the IF200 group after treatment. The percentage change at L1-3 was less (P=.04) in the IF200 group when compared to the IF100 group. A relatively uniform direction of bone formation in expanding the weight and area with different rates of change resulted in different BMD changes. Both indicated a change of bone formation patterns with the higher-dose supplement. A protective effect of IF100 on estrogen-related bone loss was observed. A lack of a benefit such as high safety in the IF200 group for 1-year administration was ensured and lacked undesirable side effects.

Short course of prophylactic antibiotics in laparoscopically assisted vaginal hysterectomy.

OBJECTIVE: To evaluate whether a short course of prophylactic antibiotics is as efficacious as a longer course in laparoscopically assisted vaginal hysterectomy (LAVH). STUDY DESIGN: A total of 156 patients who underwent LAVH were included in the study; 82 received a long course of combined prophylactic antibiotics, and 74 received a short course, administered for < 24 hours during the perioperative period. The subjects were randomly assigned using a computer-generated schedule. Data regarding resource consumption were collected from the hospital's electronic database. Patient characteristics and medical care process data were collected from the patient charts. Student's t test was used to determine the statistical significance of the differences between continuous variables in the 2 groups of patients. The chi2 test was used to measure the statistical significance of differences between nominal variables in the 2 groups. RESULTS: The short course significantly influenced the number of injected vials of antibiotics, the antibiotic fee and the total admission fee. The average total admission fee decreased by 2.3% (p = 0.034), and the average antibiotic-fee dropped by 68.4% (p < 0.01). The average injected vials of cephalothin decreased by 4.3, and the vials of gentamycin decreased by 3.3 (p < 0.01). As for the rate of operative site infection and urinary tract infection during hospitalization and within 7 days of discharge, no statistical differences were found between the 2 groups (p = 0.735; p = 0.917). CONCLUSION: This pilot study revealed that a short course of prophylactic antibiotics was as efficacious as a longer course in preventing postoperative infection. It was also cost-effective.

Identification of the cadherin subtypes present in the human peritoneum and endometriotic lesions: potential role for P-cadherin in the development of endometriosis.

Endometriosis is defined as endometrial tissue outside of the uterine cavity. The pathogenesis of this common disease remains poorly understood. However, the implantation and invasion of the viable cells from retrograde menstruation into the peritoneum is a widely accepted theory. To date, the mechanisms by which cell adhesion molecules mediate the development of human endometriosis remain unclear. Cadherins are a family of cell adhesion molecules that mediate cell-cell adhesion in a homophilic manner. In this study, the cadherins present in the peritoneum and endometriotic lesions were identified by RT-PCR using degenerate primers. In addition, differences in the levels of the cadherin mRNA transcripts present in eutopic endometrium and endometriotic lesions of the same patients were then compared by semiquantitative RT-PCR. Multiple cadherins were detected in the peritoneum and endometriotic lesions. Of these, P-cadherin appears to be the predominant cadherin subtype present in the peritoneum. Similarly, P-cadherin mRNA levels in endometriotic lesions were significantly greater than those observed in the corresponding eutopic endometrium. The expression of P-cadherin in both the human peritoneum and endometriotic lesions suggests that this cell adhesion molecule may play a central role in the development of endometriosis by mediating endometrial-peritoneal cell interactions in a homophilic manner.