Risk of placenta accreta spectrum following myomectomy: a nationwide cohort study.

BACKGROUND: Whether myomectomy increases the risk of placenta accreta spectrum in the following pregnancies remains controversial. OBJECTIVE: This study aimed to investigate the effect of myomectomy on the risk of placenta accreta spectrum in the following pregnancies. Moreover, different methods of myomectomy on the risk of placenta accreta spectrum were explored. STUDY DESIGN: A nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database, including all pregnant patients in Taiwan who gave birth between January 2008 and December 2017. A 1:1 propensity score estimation matching was performed for the analysis of myomectomy on the risk of placenta accreta spectrum. Among pregnant patients who received myomectomy, different methods of myomectomy on the risk of placenta accreta spectrum were compared with the control group. RESULTS: Among the 1,371,458 pregnant patients in this study, 11,255 pregnant patients had a history of myomectomy. The risk of placenta accreta spectrum was higher in pregnant patients with a history of myomectomy than in pregnant patients without a history of myomectomy (incidence: 0.96% vs 0.20%; adjusted odds ratio, 2.28; 95% confidence interval, 1.85-2.81; P<.01). Among pregnant patients with a history of myomectomy, 5045 (46.87%) received laparotomic myomectomy, 3973 (36.93%) received laparoscopic myomectomy, and 1742 (16.20%) received hysteroscopic myomectomy. The incidence of placenta accreta spectrum was higher in the hysteroscopic group than in the laparotomic group or the laparoscopic group (1.89% [hysteroscopic group] vs 0.71% [laparotomic group] and 0.81% [laparoscopic group]; P<.05). Compared with patients without a history of myomectomy, the adjusted odds ratio for placenta accreta spectrum was 3.88 (95% confidence interval, 2.68-5.63; P<.05) in the hysteroscopic group. CONCLUSION: Myomectomy, especially hysteroscopic myomectomy, is associated with an increased risk of placenta accreta spectrum in the subsequent pregnancy.

Disordered hypothalamus-pituitary-ovary axis in heterotopic extraovarian sex cord-stromal proliferation: a case report of fallopian tube serous adenofibroma.

BACKGROUND: Fallopian tube serous adenofibromas are uncommon tumors of the female genital tract, only dozens of cases have ever been reported. Earlier study indicated that they might be derived from embryonic remnants of the Müllerian duct. Clinical presentation of these tumors is usually asymptomatic. Small cysts of 0.5-3 cm in diameter are mostly incidentally found at the fimbriae end, with coarse papillary excrescences lined by epithelial cells and connective tissue stroma without nuclear pleomorphism or mitosis. CASE PRESENTATION: A 23-year-old woman with normal secondary sexual characters and 46, XX karyotype, presented to the gynecology clinic complaining of irregular menstrual cycles. Laboratory studies reported unique discrepancy of hormone levels; anti-Müllerian hormone (AMH): 6.05 ng/mL (The normal range of AMH is 1.70-5.63 ng/mL in women aged under 35 years old), follicle stimulating hormone (FSH): 31.9 mIU/mL (reference range: 3.85-8.78, follicular phase; 4.54-22.51, ovulatory phase; 1.79-5.12, luteal phase; 16.74-113.59, menopause), and luteinizing hormone (LH): 52.0 mIU/mL (reference range: 2.12-10.89, follicular phase; 19.18-103.03, ovulatory phase; 1.20-12.86, luteal phase; 10.87-58.64, menopause), mimicking gonadotropin-resistant ovary syndrome. The ultrasound reported a right adnexal cyst of 10.4 × 7.87 × 6.7 cm. Laparoscopic evaluation was performed; pathology revealed serous adenofibroma of the fallopian tube with ovarian stroma contents. Heterotopic extraovarian sex cord-stromal proliferations was most probable. The patient's hormone levels returned to the reproductive status two weeks after surgery; FSH: 7.9 mIU/mL, LH: 3.59 mIU/mL,and AMH: 4.32 ng/mL. The patient's menstrual cycles have resumed to normal for over two years after removal of the fallopian tube cyst. CONCLUSIONS: This case of fallopian tube serous adenofibromas presented a discrepancy of serum AMH and FSH mimicking gonadotropin-resistant ovary syndrome. The clinical picture derived from heterotopic extraovarian sex cord-stromal proliferation indicated a disordered hypothalamus-pituitary-ovary axis.

Aggressive Cervical Dilation Exploits Potential Weakness in the Septum of Duplicated Cervix during Hysteroscopic Cervix-preserving Metroplasty of Complete Septate Uterus: A Cohort Study.

STUDY OBJECTIVE: To evaluate whether aggressive cervical dilation is effective for creating the initial perforation between noncommunicating cavities of the complete septate uterus (CSU), which serves as the first step of hysteroscopic cervix-preserving metroplasty (CPM). DESIGN: A retrospective cohort. SETTING: A tertiary referral center. PATIENTS: Fifty-three patients with CSU were diagnosed using vaginal examinations, combined two- and three-dimensional vaginal ultrasounds, and office-based hysteroscopies. INTERVENTIONS: Patients who had received hysteroscopic CPM with the initial perforation created by aggressive cervical dilation or by the traditional method of bougie-guided incisions were compared. MEASUREMENTS AND MAIN RESULTS: Of the 53 patients with CSU, 44 patients received hysteroscopic CPM that required the creation of a perforation. Patients who received aggressive cervical dilation for creation of the perforation had nonsignificantly shorter surgical times (33.5 minutes, 95% confidence interval [CI], 28.4-38.6 vs 48.7 minutes, 95% CI, 28.2-71.3, p = .099), used significantly lower volumes of distending media (3.6 liters, 95% CI, 3.1-4.1 vs 6.8 liters, 95% CI, 4.2-9.3, p <.001), and had higher success rates (84.4%, 95% CI, 67.2-94.7 vs 50.0%, 95% CI, 21.1-78.9, p = .019). The sites of perforation all occurred on the endocervical septum and were generally fibrous and avascular. CONCLUSION: We present a novel, effective method for creating the initial perforation in hysteroscopic CPM. The success may be because of the existence of a potential weakness in the septum of the duplicated cervix, which spontaneously tears upon aggressive mechanical dilation. The method forgoes the risks associated with sharp incisions based on potentially unreliable cues and may greatly simplify the procedure.

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.

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.

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model.

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.

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.

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.

Intentional endometrial injury increases embryo implantation potentials through enhanced endometrial angiogenesis†.

Embryo implantation rates have been found to be enhanced by precedent endometrial injuries, but the underlying mechanism is not fully investigated. Endometrial inflammation occurs both at peri-implantation period and after endometrial injury, in which vascular reaction is a distinctive feature of inflammation. In this study, intentional endometrial injury was done with a 0.7-mm-diameter brush inserted into the left uterine horn of female ICR mice, then turned around 720° (group 2), and the right uterine horn served as the controls without endometrial injuries (group 1). Intraperitoneal equine chorionic gonadotropin 2.5 IU was injected, followed by human chorionic gonadotropin 10 IU injection, and the uterus was dissected 5 days later, roughly at the peri-implantation period. The peri-implantation endometrium was obtained, and angiogenesis protein array revealed that matrix metalloproteinase-3 (MMP-3), plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor binding protein 1 (IGFBP-1), and IL-1α were more strongly expressed in injured endometrium (group 2) than in the controls (group 1). Immunohistochemical CD34 staining was more prominently expressed in group 2 uterus, and the treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly decreased CD34 immunopositive cells. The capabilities of permeability, proliferation, tube formation, and migration of mouse endometrial endothelial cells were significantly enhanced in group 2 than in group 1. Our results demonstrate that enhanced endometrial angiogenesis is a possible mechanism accounting for the increased endometrial receptivity after endometrial injury.

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.

Concordance between different trophectoderm biopsy sites and the inner cell mass of chromosomal composition measured with a next-generation sequencing platform.

STUDY QUESTION: In PGS, does chromosomal constitution differ among trophectoderm (TE) biopsy sites and between them and the inner cell mass (ICM)? SUMMARY ANSWER: The ploidy concordance between ICM and TE was independent of whether the biopsy site in the TE was near to or far from the ICM. WHAT IS KNOWN ALREADY: TE biopsies are considered less harmful to developing embryos than blastomere biopsies. Removal of multi-cellular samples permits high-resolution next-generation sequencing (Veriseq NGS) to detect aneuploidy present in a minority of cells (mosaicism of diploid and aneuploid cells). However, the prevalence of ploidy discrepancies between different TE biopsy sites and the ICM, as well as confined mosaicism (aneuploidy only in a particular area), has not been established. STUDY DESIGN, SIZE, DURATION: Biopsies were taken from a site opposite to the ICM (TE1), near the ICM (TE2) and within the ICM of the same embryo in 33 donated blastocysts obtained from 12 volunteer patients. The samples were analyzed by the Veriseq NGS to assess ploidy concordance. PARTICIPANTS/MATERIALS, SETTING, METHODS: The mean age of the patients was 34.4 years, and samples from all three biopsy sites were achieved in 29 frozen thawed blastocysts. The aneuploid percentage in each sample was interpreted by Veriseq NGS at the finest resolution involving the number of reads after filtering, sample overall noise score, and average quality/alignment scores according to the Veriseq quality control assessment. Ploidy concordance was then assessed between different TE fractions, and between the TE and ICM. MAIN RESULTS AND THE ROLE OF CHANCE: The euploid rates were similar in the TEs and ICM, and no preferential allocation of euploid lineage within a blastocyst was demonstrated. Whether the biopsy site in the TE was near to or far from the ICM, the chromosomal consistency rate was similar [TE1-to-ICM, 86.2% (25/29) versus TE2-to-ICM, 89.7% (26/29); P = 1.0], suggesting that the cells with different chromosomal components may spread randomly throughout the TE. The following two types of inconsistent PGS conclusions between TE and ICM due to confined mosaicism were observed: (i) euploid TE with mosaic ICM (3%) (1/29); and (ii) mosaic TE with euploid ICM (3%) (1/29) or with aneuploid ICM (7%) (2/29). Thus, the overall rate of confined mosaicism was 14% (4/29). LARGE SCALE DATA: N/A. LIMITATION, REASONS FOR CAUTION: The approach used in the present study was affected by biopsy manipulation limitations involving possible cell contamination and the technical challenge of comprehensive chromosomal screening (CCS) procedures. WIDER IMPLICATIONS OF THE FINDINGS: The rate of confined mosaicism in the blastocysts was estimated in this preliminary study, thus, specifying the incidence of biological sampling biases. The results also verified the random distribution of different cell lineages, and the representative value of a single biopsied sample from the TE. STUDY FUNDING AND CONFLICT OF INTEREST(S): No external funding was obtained; all the authors declare no conflicts of interest regarding this study.

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.

Preimplantation genetic diagnosis and screening: Current status and future challenges.

Preimplantation genetic diagnosis (PGD) is a clinically feasible technology to prevent the transmission of monogenic inherited disorders in families afflicted the diseases to the future offsprings. The major technical hurdle is it does not have a general formula for all mutations, thus different gene locus needs individualized, customized design to make the diagnosis accurate enough to be applied on PGD, in which the quantity of DNA is scarce, whereas timely result is sometimes requested if fresh embryo transfer is desired. On the other hand, preimplantation genetic screening (PGS) screens embryo with aneuploidy and was also known as PGD-A (A denotes aneuploidy) in order to enhance the implantation rates as well as livebirth rates. In contrasts to PGD, PGS is still under ferocious debate, especially recent reports found that euploid babies were born after transferring the aneuploid embryos diagnosed by PGS back to the womb and only very few randomized trials of PGS are available in the literature. We have been doing PGD and/or PGS for more than 10 years as one of the core PGD/PGS laboratories in Taiwan. Here we provide a concise review of PGD/PGS regarding its current status, both domestically and globally, as well as its future challenges.

Feasibility of corifollitropin alfa/GnRH antagonist protocol combined with GnRH agonist triggering and freeze-all strategy in polycystic ovary syndrome patients.

BACKGROUND/PURPOSE: The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients. METHODS: Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles. RESULTS: All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (±7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (±6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (±3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%). CONCLUSION: The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation.

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.

Value and application of trimodality therapy or definitive concurrent chemoradiotherapy in thoracic esophageal squamous cell carcinoma.

BACKGROUND: Few large, prospective, randomized studies have investigated the value and optimal application of neoadjuvant chemoradiotherapy followed by surgery (trimodality therapy) or definitive concurrent chemoradiotherapy (CCRT) for patients with thoracic esophageal squamous cell carcinoma (TESCC). METHODS: The authors analyzed data from patients with TESCC in the Taiwan Cancer Registry database. To compare their outcomes, patients with TESCC were enrolled and categorized into the following groups according to treatment modality: group 1, those who underwent surgery alone; group 2, those who received trimodality therapy; and group 3, those who received definitive CCRT. Group 1 was used as the control arm for investigating the risk of mortality after treatment. RESULTS: In total, 3522 patients who had TESCC without distant metastasis were enrolled. Multivariate Cox regression analysis indicated that a Charlson comorbidity index score ≥3, American Joint Committee on Cancer stage ≥IIA, earlier year of diagnosis, alcohol consumption, cigarette smoking, and definitive CCRT were significant, independent predictors of a poor prognosis. After adjustment for confounders, adjusted hazard ratios and 95% confidence intervals (CIs) for overall mortality in patients with clinical stage I, IIA, IIB, IIIA, IIIB, and IIIC TESCC were 2.01 (95% CI, 0.44-6.18), 1.65 (95% CI, 0.99-2.70), 1.48 (95% CI, 0.91-2.42), 0.66 (95% CI, 1.08-1.14), 0.39 (95% CI, 0.26-0.57), and 0.44 (95% CI, 0.24-0.83), respectively, in group 2; and 2.06 (95% CI, 1.18-3.59), 2.65 (95% CI, 1.76-4.00), 2.25 (95% CI, 1.49-3.39), 1.34 (95% CI, 0.79-2.28), 0.82 (95% CI, 0.57-1.17), and 0.93 (95% CI, 0.51-1.71), respectively, in group 3. CONCLUSIONS: Trimodality therapy may be beneficial for the survival of patients with advanced-stage (IIIA-IIIC) TESCC, and CCRT might be an alternative to surgery alone in these patients. Cancer 2017;123:3904-15. © 2017 American Cancer Society.

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.