Publications by authors named "Keiji Kuroda"

65 Publications

Optimal individualization of patient-oriented ovarian stimulation in Japanese assisted reproductive technology clinics, a review for unique setting with advanced-age patients.

J Obstet Gynaecol Res 2022 Jan 13. Epub 2022 Jan 13.

Department of Obstetrics and Gynecology, Saitama Medical University, Saitama, Japan.

Ovarian stimulation is a key issue in assisted reproductive technology (ART) treatment. ART practice in Japan is unique with various types of ovarian stimulation protocols, which may contribute to lower pregnancy rates compared to other countries. This review aims to clarify optimal individualized ovarian stimulation for improving the pregnancy rate per one oocyte retrieval cycle in Japan. We performed a literature review to describe ovarian stimulation, classification of infertile women depending on ovarian reserve and response, and Japanese ART data and discussed optimal conventional and mild ovarian stimulation protocols in Japan. According to Japanese ART registry data, the live birth rate of 30-35-year-old women was 32%-37% per ET cycle; therefore, four to five embryos are calculatedly needed when aiming a cumulative live birth rate of ≥80%. Mild stimulation aimed at collecting 5-10 oocytes can be alternative choice as an optimal ovarian stimulation protocol in young women. In 40-year-old women, the live birth rate is 18.8%, resulting in eight or more embryos as necessary. Conventional stimulation must be required in women with advanced age. In poor responders, however, mild stimulation may be sufficient for maximumly extracting their ovarian function. In Japan, mild ovarian stimulation can be selected in patients with a good prognosis and poor responders; however, conventional ovarian stimulation is necessary for women in advanced age.
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http://dx.doi.org/10.1111/jog.15150DOI Listing
January 2022

Therapeutic effects of an oral gonadotropin-releasing hormone receptor antagonist, relugolix, on preventing premature ovulation in mild ovarian stimulation for IVF.

Reprod Med Biol 2022 Jan 19;21(1):e12422. Epub 2021 Oct 19.

Center for Reproductive Medicine and Implantation Research Sugiyama Clinic Shinjuku Tokyo Japan.

Purpose: Can relugolix, a novel oral gonadotropin-releasing hormone receptor (GnRH) antagonist, function as an alternative ovulation inhibitor to GnRH antagonist injections?

Methods: This single-center, cross-sectional retrospective study compared premature ovulation rates and clinical outcomes in IVF treatment after mild ovarian stimulation with 40 mg of relugolix (relugolix group) or 0.25-mg injections of ganirelix acetate or cetrorelix acetate (injection group) between March 2019 and January 2020. Of 247 infertile women (256 IVF cycles) aged ≤42 years, 223 women (230 cycles) were evaluated. In the relugolix and injection groups, we compared 104 and 85 cycles after GnRH antagonist use before the LH surge (LH levels <10 mIU/ml) and 22 and 19 cycles during the LH surge (LH levels ≥10 mIU/ml), respectively.

Results: Before the LH surge, the ovulation rates in the two groups were very low ( = 0.838), however; during the LH surge, the cycles using relugolix had a high ovulation rate of 40.9% compared with no ovulation in the injection group ( = 0.002). There were no significant differences in embryo culture findings and pregnancy outcomes between the two groups.

Conclusions: Although relugolix had a high ovulation suppressive effect, when the LH surge occurred, its effect was insufficient.
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http://dx.doi.org/10.1002/rmb2.12422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656665PMC
January 2022

Novel approaches to the management of recurrent pregnancy loss: The OPTIMUM (OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu) treatment strategy.

Reprod Med Biol 2021 Oct 14;20(4):524-536. Epub 2021 Sep 14.

Centre for Reproductive Medicine and Implantation Research Sugiyama Clinic Shinjuku Tokyo Japan.

Purpose: Does the OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy, developed for treating repeated implantation failure (RIF), contribute to improving pregnancy outcomes in patients with a history of recurrent pregnancy loss (RPL)?

Methods: Between 2018 and 2019, women with RPL after two or more clinical pregnancy losses underwent RPL testing. We treated chronic endometritis with antibiotics, high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of 168 consecutive women aged ≤43 years, 115 underwent RPL testing. We compared 100 pregnancies (90 women) and 46 pregnancies (41 women) with and without the OPTIMUM treatment strategy, respectively.

Results: RPL testing identified intrauterine abnormalities in 66 (57.4%), elevated Th1/Th2 cell ratios in 50 (43.5%), thyroid dysfunction in 33 (28.7%), and thrombophilia in 33 (28.7%). The live birth rate in the OPTIMUM group was significantly higher than that in the control group among women aged <40 years (78.1% and 42.3%, respectively;  = 0.002), but no significant difference was observed in women aged ≥40 years (55.6% and 30.0%, respectively;  = 0.09).

Conclusions: The OPTIMUM treatment strategy improved pregnancy outcomes in patients with not only RIF but also RPL.
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http://dx.doi.org/10.1002/rmb2.12412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499598PMC
October 2021

Heterodyne detection applied to a fiber Bragg grating-based sensor using a directly modulated distributed feedback laser.

Authors:
Keiji Kuroda

Opt Lett 2021 Aug;46(16):3985-3988

The heterodyne detection technique is applied to a fiber Bragg grating (FBG)-based sensor. Specifically, a directly modulated distributed feedback laser array is used as a frequency scanning light source. Weak reflections from the FBG are recorded as a beat signal with a high signal-to-noise ratio using heterodyne detection. A reflection signal is clearly observed from the FBG with a reflectivity of 1% located at 60 km from the detection port.
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http://dx.doi.org/10.1364/OL.432915DOI Listing
August 2021

Analysis of vaginal and endometrial microbiota communities in infertile women with a history of repeated implantation failure.

Reprod Med Biol 2021 Jul 31;20(3):334-344. Epub 2021 May 31.

Saint Mother Obstetrics and Gynecology Clinic and Institute for Assisted Reproductive Technologies Fukuoka Japan.

Purpose: To identify specific bacterial communities in vaginal and endometrial microbiotas as biomarkers of implantation failure by comprehensively analyzing their microbiotas using next-generation sequencing.

Methods: We investigated α- and β-diversities of vaginal and endometrial microbiotas using 16S rRNA gene sequencing and compared their profiles between 145 women with repeated implantation failure (RIF) and 21 controls who lacked the factors responsible for implantation failure with a high probability of being healthy and fertile to identify specific bacteria that induce implantation failure.

Results: The endometrial microbiotas had higher α-diversities than did the vaginal microbiotas ( < .001). The microbiota profiles showed that vaginal and endometrial samples in RIF patients had significantly higher levels of 5 and 14 bacterial genera, respectively, than those in controls. Vaginal rates in RIF patients were significantly lower at 76.4 ± 38.9% compared with those of the controls at 91.8 ± 22.7% ( = .018), but endometrial rates did not significantly differ between the RIF patients and controls (56.2 ± 36.4% and 58.8 ± 37.0%, respectively,  = .79).

Conclusions: Impaired microbiota communities containing specific bacteria in both the endometrium and vagina were associated with implantation failure. The vaginal rates, but not the endometrial, may be a biomarker for RIF.
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http://dx.doi.org/10.1002/rmb2.12389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254176PMC
July 2021

Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women.

Nutrients 2021 Apr 20;13(4). Epub 2021 Apr 20.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo 116-0023, Japan.

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.
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http://dx.doi.org/10.3390/nu13041381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073279PMC
April 2021

Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio.

Am J Reprod Immunol 2021 09 20;86(3):e13429. Epub 2021 Apr 20.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.

Problem: We aimed to assess whether an imbalance of T-helper (Th) 1 and Th2 cells contributes to implantation failure and pregnancy loss.

Method Of Study: In this cross-sectional study, 197 consecutive patients with a history of repeated implantation failure (RIF) after three or more embryo transfer (ET) cycles and/or recurrent pregnancy loss (RPL) after two or more clinical pregnancy losses underwent Th cell testing. After excluding 42 women aged ≥44 and 9 with vitamin D supplementation, we recruited 146 women including 79 with RIF and 81 with RPL. Fourteen women had a history of both RIF and RPL. We also recruited 45 fertile women and 40 general infertile women without a history of in vitro fertilization treatment. This study was approved by the local ethics committee.

Results: There was no significant difference in IFN-γ-producing Th1 and IL-4-producing Th2 cell levels between the fertile and general infertile women, but Th1 cell levels and the Th1/Th2 cell ratio were significantly higher in the women with ≥4 ET cycles and ≥2 pregnancy losses than in the fertile and general infertile women. In the general infertile women, the total livebirth rates including natural conception after two ET cycles in the normal and high Th1/Th2 groups (Th1/Th2 <11.8 and ≥11.8, respectively) were 66.7% and 87.5%, respectively (p = .395).

Conclusions: A high Th1/Th2 cell ratio was linked to ≥4 implantation failure cycles and ≥2 pregnancy losses but not to general infertility.
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http://dx.doi.org/10.1111/aji.13429DOI Listing
September 2021

Analysis of the therapeutic effects of hysteroscopic polypectomy with and without doxycycline treatment on chronic endometritis with endometrial polyps.

Am J Reprod Immunol 2021 06 27;85(6):e13392. Epub 2021 Jan 27.

Center for Reproductive Medicine and Endoscopy, Sugiyama Clinic Marunouchi, Tokyo, Japan.

Problem: We aimed to compare the therapeutic effects of hysteroscopic polypectomy with and without doxycycline treatment on chronic endometritis (CE) with endometrial polyps.

Method Of Study: DESIGN: A cross-sectional study was conducted on 267 infertile patients, of whom 243 were recruited, who underwent hysteroscopic polypectomy between March 2019 and March 2020. During surgery, the endometrial specimens for the immunohistochemistry analysis of the plasma cell marker CD138 and for the intrauterine bacterial culture were obtained to diagnose CE, and the prevalence of CE was analyzed. Of the 222 women who were diagnosed with CE after polypectomy, we treated 62 women with doxycycline (antibiotic group) and did not provide antibiotics in 160 women (non-antibiotic group).

Results: Most of the infertile patients with endometrial polyps had CE (92.6%). The recovery rate from CE by hysteroscopic polypectomy was significantly higher in the non-antibiotic group than in the antibiotic group (88.8% and 58.1%, respectively, p < 0.0001). The duration of recovery from CE in the non-antibiotic group was shorter than that in the antibiotic group (42.6 ± 41.0 and 56.5 ± 32.3 days, respectively, p < 0.0001). The clinical pregnancy rate within 6 months in non-antibiotic group was higher than that in the antibiotic group (63.2% and 43.8%, respectively, p = 0.034).

Conclusion: Endometrial polyps are significantly associated with CE. Most CE patients with endometrial polyps had been cured by polypectomy without doxycycline. Inappropriate antibiotic therapy may delay recovery from CE and decrease the efficacy of polypectomy on CE and pregnancy rates.
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http://dx.doi.org/10.1111/aji.13392DOI Listing
June 2021

Analysis of severe psychological stressors in women during fertility treatment: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study.

Arch Gynecol Obstet 2021 07 1;304(1):253-261. Epub 2021 Jan 1.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Purpose: To identify risk factors for severe psychological stress in women undergoing fertility treatment.

Methods: This cross-sectional, multi-center study was conducted from August to December 2018. We recruited 1672 subjects who completed an anonymous, self-reported questionnaire regarding fertility treatment, conditions at work and home, and psychological stress using K6 score, which estimates psychological distress during the previous 30 days. We further focused our analysis on 1335 subjects who were working when starting fertility treatment.

Results: Of 1672 women, mean K6 score (range 0-24) was 4.8 ± 4.4, including 103 women (6.2%) with K6 score ≥ 13 (high K6), and classified as probable severe psychological distress. Multivariate logistic regression analysis showed that high K6 was strongly associated with low annual family income of ≤ USD55,700 (JPY6 million) (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.04-3.42), infertility duration of ≥ 2 years (OR 1.87, 95% CI 1.08-3.25), and no experience of childbirth (OR 2.04, 95% CI 1.05-3.97). Focusing on 1335 working women, 266 (19.9%) experienced resignation from work. High K6 was strongly associated with low family income (OR 2.83, 95% CI 1.52-5.28), cessation of professional duties (OR 2.08, 95% CI 1.05-4.14), infertility-related harassment in the workplace (OR 2.07, 95% CI 1.08-3.98), and perceived difficulties to continue working during fertility treatment (OR 2.94, 95% CI 1.15-7.50).

Conclusion: Severe psychological stressors in women during fertility treatment included low family income, long infertility duration, childlessness, infertility-related harassment, and perceived difficulty in working conditions or cessation from work. Establishment of mental health care support systems is urgently required in this population.
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http://dx.doi.org/10.1007/s00404-020-05923-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775729PMC
July 2021

Risk factors for resignation from work after starting infertility treatment among Japanese women: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study.

Occup Environ Med 2020 Dec 3. Epub 2020 Dec 3.

Department of Public Health, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Objective: To elucidate the risk factors associated with resignation from work of Japanese women undergoing infertility treatment.

Methods: A total of 1727 female patients who attended a private fertility clinic in Japan participated in the Japan-Female Employment and Mental health in Assisted reproductive technology study. Questions related to demographic, clinical and socioeconomic characteristics were employed in the questionnaire. Out of the 1727 patients, 1075 patients who were working at the time of initiating infertility treatment and felt infertility treatment incompatible with work were included in the analysis. Risk factors for resignation were assessed by using multivariable logistic regression models.

Results: Among 1075 working women who started infertility treatment, 179 (16.7%) subsequently resigned. Multivariable-adjusted ORs for resignation in those with lower educational background and infertility for ≥2 years were 1.58 (95% CI: 1.07 to 2.34) and 1.82 (95% CI: 1.15 to 2.89), respectively. The OR for resignation in non-permanent workers undergoing infertility treatment was 2.65 (95% CI: 1.61 to 4.37). While experiencing harassment in the workplace approached significance, lack of support from the company was significantly associated with resignation after starting infertility treatment, with ORs of 1.71 (95% CI: 0.98 to 2.99) and 1.91 (95% CI: 1.28 to 2.86), respectively.

Conclusion: One-sixth of women resigned after starting infertility treatments. It was found that factors related to education, infertility duration and work environment were significantly associated with resignation. Reducing the physical and psychological burden endured by women, for example, by increasing employer-provided support, is vitally important in balancing infertility treatment with maintenance of work life.
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http://dx.doi.org/10.1136/oemed-2020-106745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142458PMC
December 2020

Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy.

Am J Reprod Immunol 2021 05 27;85(5):e13376. Epub 2020 Nov 27.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.

Problem: What are the pregnancy outcomes after the OPtimization of Thyroid function, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)?

Method Of Study: Infertile women with a history of RIF after more than three embryo transfer (ET) cycles underwent implantation testing, including a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and serum 25-hydroxyvitamin D , interferon-γ-producing helper T (Th1) cell, IL-4-producing helper T (Th2) cell, thyroid-stimulating hormone, thyroid peroxidase antibody, and thrombophilia screening between April 2017 and August 2018. We treated chronic endometritis with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus intake, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of the 116 RIF women, 88 women with 133 ET cycles were recruited from a questionnaire-based survey regarding pregnancy outcomes. Fifty-nine consecutive RIF patients without the OPTIMUM treatment strategy were also recruited as a control.

Results: The 116 women with RIF after the OPTIMUM treatment strategy were 38.3 ± 3.8 years old and had an implantation failure history over 5 (3-19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged < 40 and ≥ 40 years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control.

Conclusions: The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.
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http://dx.doi.org/10.1111/aji.13376DOI Listing
May 2021

Incidences and risk factors of moderate-to-severe ovarian hyperstimulation syndrome and severe hemoperitoneum in 1,435,108 oocyte retrievals.

Reprod Biomed Online 2021 Jan 3;42(1):125-132. Epub 2020 Sep 3.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo 116-0023, Japan.

Research Question: What are the risk factors affecting the incidences of moderate-to-severe ovarian hyperstimulation syndrome (OHSS) and severe hemoperitoneum in assisted reproductive technology (ART) treatment cycles?

Design: A retrospective cohort study was conducted on 1,435,108 oocyte retrieval cycles among Japanese ART registry data between 2007 and 2015. The study included 11,378 cycles with moderate-to-severe OHSS, 1182 cycles with severe hemoperitoneum, including 27 cycles with both conditions, and 1,422,575 cycles without moderate-to-severe OHSS and severe hemoperitoneum.

Results: The incidences of moderate-to-severe OHSS and severe hemoperitoneum were 0.79% and 0.08%, respectively, and decreased by 0.57-fold and 0.29-fold from 2007 to 2015, respectively. In cycles with OHSS and cycles with hemoperitoneum women were younger (odds ratios [OR] 0.91 and 0.95, respectively) and had more retrieved oocytes (OR 1.09 and 1.01, respectively) compared with cycles without both complications. The use of a gonadotrophin-releasing hormone (GnRH) agonist protocol for ovarian stimulation was the highest risk factor in cycles with OHSS and hemoperitoneum (OR 1.83 and 1.24, respectively), followed by GnRH antagonist protocol (reference), gonadotrophin with or without oral medicine (OR 0.45 and 0.56, respectively) and natural or oral medicine (OR 0.02 and 0.19, respectively). In fresh embryo transfer, clinical pregnancy was associated with an increased risk of OHSS and hemoperitoneum (OR 1.19 and 2.34, respectively).

Conclusions: The highest risk factors affecting OHSS and hemoperitoneum were the use of a GnRH agonist protocol and clinical pregnancy following fresh embryo transfer. The incidences of OHSS and hemoperitoneum have decreased yearly with a reduction of GnRH agonist use and fresh embryo transfer.
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http://dx.doi.org/10.1016/j.rbmo.2020.09.001DOI Listing
January 2021

The actions of resveratrol in decidualizing endometrium: acceleration or inhibition?†.

Biol Reprod 2020 12;103(6):1152-1156

The Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, Coventry, UK.

Resveratrol, a natural polyphenolic compound, is widely studied for its anti-inflammatory and antisenescent properties. Recently, two studies reported seemingly conflicting findings on the actions of resveratrol on decidualization of human endometrial stromal cells (HESCs). One study by Ochiai et al. demonstrated that resveratrol inhibits decidual transformation of primary cultured HESCs. The other study by Mestre Citrinovitz et al., showed that resveratrol enhances decidualization of HESCs in culture. At a glance, the reason for these opposing observations seems puzzling. However, recent studies demonstrated that decidualization is a multistep process, which starts with an acute proinflammatory stress response that lasts for several days and is followed by the emergence of stress-resistant decidual cells as well as senescent decidual cells. The balance between these decidual subpopulations may determine if the cycling endometrium can successfully transition into the decidua of pregnancy upon embryo implantation. Here, we explore the importance of timing of drugs aimed at modulating the decidual response. We posit that resveratrol treatment during the initial proinflammatory decidual phase, i.e., coinciding with the implantation window in vivo, inhibits decidual transformation of the endometrium. However, when given after the initial phase, resveratrol may promote decidualization by inhibiting decidual senescence. Further, if restricted to the proliferative phase, resveratrol may promote ovarian function without adversely impacting on embryo implantation or decidualization. Thus, failure to align drug interventions with the correct phase of the menstrual cycle may negate beneficial clinical effects and results in adverse reproductive outcomes.
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http://dx.doi.org/10.1093/biolre/ioaa172DOI Listing
December 2020

Effect of thyroxine treatment on pregnancy outcomes in infertile Japanese women with TSH levels between 2.5 μIU/mL and the upper reference limit: a retrospective study.

Endocr J 2021 Feb 1;68(2):171-177. Epub 2020 Oct 1.

Department of Metabolism & Endocrinology, Juntendo University Graduate School, Tokyo 113-8421, Japan.

Recent randomized controlled studies have revealed that levothyroxine (LT4) treatment improves pregnancy outcomes only in infertile women with subclinical hypothyroidism who have thyroid autoantibodies (TAs), but not for those with high TSH levels within the normal range who have TAs. Here, we retrospectively investigated pregnancy outcomes in infertile Japanese women with 2.5 μIU/mL ≤ TSH < upper reference limit (URL). Between 2012 and 2018, 286 patients diagnosed with infertility were followed for more than 1 year at our institution. Among them, we included 106 patients with 2.5 μIU/mL ≤ TSH < URL. We divided these patients into four groups based on the combination of TA positivity and LT4 treatment status to assess the effects of LT4 treatment considering TA positivity on the incidence of pregnancy or miscarriage. In this study, we did not find any significant differences in the rates of pregnancy or miscarriage among the four groups (p = 0.81 and 0.52, respectively). In addition, logistic regression analysis showed that age and history of miscarriage were associated with the incidence of pregnancy, but presence of TAs and LT4 treatment status were not and that no variables examined were associated with the incidence of miscarriage. In summary, we were not able to demonstrate the benefit of LT4 treatment for pregnancy outcomes in Japanese euthyroid infertile women with 2.5 μIU/mL ≤ TSH < URL regardless of TA status in this study.
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http://dx.doi.org/10.1507/endocrj.EJ20-0380DOI Listing
February 2021

Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes.

Immun Inflamm Dis 2020 12 23;8(4):650-658. Epub 2020 Sep 23.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.

Background: The aim of this study is to evaluate the relationship between chronic endometritis (CE) and a personalized window of implantation (WOI), identified by results of endometrial receptivity analysis (ERA), and pregnancy outcomes following embryo transfer (ET) based on the ERA outcomes.

Methods: The single-center, cross-sectional study was designed. The study population consisted of 101 infertile women who underwent endometrial sampling between June 2018 and February 2020. We recruited 88 patients who underwent ERA testing and immunohistochemistry of the plasma cell marker CD138 to diagnose CE within 3 months of testing. Subjects were divided into three groups as follows: 33 without CE (non-CE group); 19 with untreated CE at ERA testing (CE group); and 36 successfully treated for CE before ERA testing (cured-CE group). CE diagnosis was defined as ≥5 CD138-positive plasma cells per 10 random stromal areas at ×400 magnification.

Results: In non-CE, CE, and cured-CE groups, the numbers of CD138-positive cells were 0.7 ± 1.0, 28.5 ± 30.4, and 1.3 ± 1.3, respectively (p < .001). The rates of "receptive" endometrium in non-CE and cured-CE groups were 57.6% (19 women) and 50.0% (18 women), respectively; however, in the CE group, this rate was significantly lower than the other two groups (p = .009) at only 15.8% (3 women). After CE were treated prior or posterior to the ERA test in cured-CE or CE groups, the clinical pregnancy rates at the first ET in non-CE, CE, and cured-CE groups were 77.8% (21/27 cycles), 22.2% (4/18 cycles), and 51.7% (15/29 cycles), respectively (p < 0.001).

Conclusion: CE had detrimental effects on the individual WOI, leading to embryo-endometrial asynchrony; therefore, diagnosis and treatment of CE should be done before ERA testing.
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http://dx.doi.org/10.1002/iid3.354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654412PMC
December 2020

Preconception resveratrol intake against infertility: Friend or foe?

Reprod Med Biol 2020 Apr 12;19(2):107-113. Epub 2019 Oct 12.

Department of Obstetrics and Gynecology Faculty of Medicine Juntendo University Tokyo Japan.

Background: Resveratrol is an antiaging, antioxidant, anti-inflammatory, and insulin-sensitizing natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects in infertile women with diminished ovarian function, polycystic ovary syndrome (PCOS), or endometriosis. However, only one clinical trial in women undergoing in vitro fertilization (IVF) cycles using resveratrol has ever been reported. This review focuses on the potential therapeutic effects of resveratrol on pregnancy and on its advantages and disadvantages in pregnancy outcomes during infertility treatment.

Methods: We performed a literature review to describe the known impacts of resveratrol on the ovary and endometrium.

Results: Resveratrol upregulates sirtuin (SIRT)1 expression in ovaries, which is associated with protection against oxidative stress. It leads to the activation of telomerase activity and mitochondrial function, improving ovarian function. In the endometrium, resveratrol downregulates the CRABP2-RAR pathway leading to suppressing decidual and senescent changes of endometrial cells, which is essential for embryo implantation and placentation. Moreover, resveratrol may also induce deacetylation of important decidual-related genes.

Conclusions: Resveratrol has potential therapeutic effects for improving ovarian function; however, it also has anti-deciduogenic actions in uterine endometrium. In addition, its teratogenicity has not yet been ruled out; thus, resveratrol should be avoided during the luteal phase and pregnancy.
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http://dx.doi.org/10.1002/rmb2.12303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138940PMC
April 2020

Analysis of 122 triplet and one quadruplet pregnancies after single embryo transfer in Japan.

Reprod Biomed Online 2020 Mar 29;40(3):374-380. Epub 2019 Nov 29.

Juntendo University Faculty of Medicine, Department of Obstetrics and Gynecology, Tokyo 113-8421, Japan; Sugiyama Clinic Shinjuku, Center for Reproductive Medicine and Implantation Research, Tokyo 116-0023, Japan. Electronic address:

Research Question: What is the prevalence of triplet and quadruplet pregnancies after single embryo transfer (SET) in Japan.

Design: A retrospective observational study was conducted on 274,605 pregnancies after 937,848 SET cycles in registered assisted reproductive technology (ART) data from the Japanese ART national registry database between 2007 and 2014. A questionnaire survey of ART centres was also conducted. Data on pregnancies with embryo division into three or more after SET were analysed.

Results: According to the Japanese ART national registry database, SET resulted in 109 triplet pregnancies (0.04% of pregnancies), and the questionnaire reports from 31 centres revealed 33 triplet and one quadruplet pregnancies. After exclusion of 20 duplicated cases, 122 triplet and one quadruplet pregnancies included 46 monochorionic (one gestational sac [37.4%]), 18 dichorionic (two gestational sacs [14.6%]) and 59 trichorionic pregnancies (three gestational sacs [48.0%]). Compared with singleton pregnancies, patients with monozygotic triplet or quadruplet pregnancies were less frequently diagnosed with unexplained infertility (P = 0.004), more often received gonadotrophin injections for ovarian stimulation in 39 cases with information available (P = 0.021) and underwent more blastocyst transfers and assisted hatching (P = 0.002 and P < 0.001, respectively). The proportion of live birth, defined as at least one baby born, excluding induced abortion, was 64.6% (73/116 pregnancies) of monozygotic triplet or quadruplet pregnancies.

Conclusions: Combined Japanese ART national registry and survey data revealed 122 triplet and one quadruplet pregnancies, the majority after cryopreserved embryo transfer. Most were conceived after blastocyst transfer and often after assisted hatching, which are potential risk factors for zygotic splitting.
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http://dx.doi.org/10.1016/j.rbmo.2019.11.008DOI Listing
March 2020

Influence of resveratrol supplementation on IVF-embryo transfer cycle outcomes.

Reprod Biomed Online 2019 Aug 20;39(2):205-210. Epub 2019 Mar 20.

Centre for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.

Research Question: Does resveratrol, a polyphenolic compound, affect IVF-embryo transfer outcomes?

Design: This single-centre, cross-sectional retrospective study was designed to compare the outcomes of embryo transfer cycles in women receiving resveratrol supplementation (200 mg/day) continuously (RES group) with a control group (non-RES group). Of 8686 embryo transfer cycles, 1409 cycles with poor prognostic factors were excluded, including cycles in women aged ≥43 years and those with poor-quality embryos. The RES group (204 cycles, 102 women) was compared with the non-RES group (7073 cycles, 2958 women).

Results: After matching patients by age at the time of oocyte retrieval, grade and developmental stage of embryos, number of embryos transferred, and fresh or vitrified-warmed embryo transfer, multivariate logistic regression analysis showed that resveratrol supplementation is strongly associated with a decrease in clinical pregnancy rate [odds ratio (OR) 0.539, 95% confidence interval (CI) 0.341-0.853] and an increased risk of miscarriage (OR 2.602, 95% CI 1.070-6.325).

Conclusions: Resveratrol supplementation during embryo transfer cycles appears to be detrimental for pregnancy outcomes. An analysis of the supplementation protocol and randomized controlled studies are needed.
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http://dx.doi.org/10.1016/j.rbmo.2019.03.205DOI Listing
August 2019

Obstetric and perinatal outcome of the women with repeated implantation failures or recurrent pregnancy losses who received pre- and post-conception tacrolimus treatment.

Am J Reprod Immunol 2019 08 18;82(2):e13142. Epub 2019 Jun 18.

Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan.

Problem: Previously, we reported the clinical efficacy of tacrolimus in women with repeated implantation failures (RIF) of immune etiologies. Safety of tacrolimus in pregnant women has been reported in women with organ transplantations. However, the safety of tacrolimus for women with RIF undergoing assisted reproductive technology cycles and their babies has not been reported prior.

Method Of Study: This study is a prospective observational study of 109 women with RIF or recurrent pregnancy losses (RPL) who showed elevated peripheral blood Th1/Th2 (CD4 IFN-γ /CD4 IL-4 ) cell ratios (≥10.3). All received tacrolimus before and during pregnancy (1-4 mg/d) and delivered a live-born infant(s). Blood concentrations of tacrolimus were measured. Neuromotor development of the babies was also evaluated.

Results: Total 113 babies were born from 109 women, including four twin pregnancies. Nine pregnancies including four twins were delivered prematurely (8.3%). Two of 109 women showed obstetric complications, such as hypertensive disorder of pregnancy, and only one baby (0.9%) had a congenital abnormality. There were no differences in babies' birthweight, placental weight, and lymphocyte proportion (%) of the umbilical cord among the women with different tacrolimus dosing. Tacrolimus was detected in the maternal plasma, and its concentration did not significantly fluctuate during pregnancy while on daily administration regimen. Neuromotor development of the babies exposed to tacrolimus in utero was comparable with that of babies from the general population.

Conclusion: According to our data, tacrolimus treatment for women with RIF and RPL was not associated with obstetrical and perinatal complications. A large size study is needed to confirm this finding.
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http://dx.doi.org/10.1111/aji.13142DOI Listing
August 2019

Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells.

Cell Death Dis 2019 03 20;10(4):276. Epub 2019 Mar 20.

Department of Obstetrics and Gynaecology, Faculty of Medicine, Juntendo University, Tokyo, 113-8421, Japan.

Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.
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http://dx.doi.org/10.1038/s41419-019-1511-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427032PMC
March 2019

Clinical strategies for ART treatment of infertile women with advanced maternal age.

Reprod Med Biol 2019 Jan 14;18(1):27-33. Epub 2018 Nov 14.

Center for Reproductive Medicine and Implantation Research Sugiyama Clinic Shinjuku Tokyo Japan.

Background: An ever-increasing number of women in our country with advanced maternal age are choosing to achieve pregnancy. This means effective strategies are needed for infertile patients. Questions arise, however, concerning the need for ovarian stimulation, and, if so, whether intracytoplasmic sperm injection (ICSI) is better than conventional insemination for those women who may have only one mature oocyte.

Methods: We evaluated our data to answer these questions. Herein, we also introduce our strategy for patients who show unsynchronized follicular growth.

Main Findings: Ovarian stimulation in ART treatment for patients with advanced maternal age has resulted in the achievement of higher pregnancy rates, and therefore, this form of stimulation is often selected. Based on our data, ICSI as an insemination procedure has not improved clinical pregnancy rates compared with conventional insemination and has actually decreased the clinical pregnancy rates.

Conclusion: In this article, we reviewed and compared the protocols and strategies that are available to increase the number of developed embryos for the patients with advanced maternal age. We hope that this review will be helpful for both patients and clinicians.
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http://dx.doi.org/10.1002/rmb2.12240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378758PMC
January 2019

Combination Treatment of Preoperative Embryo Cryopreservation and Endoscopic Surgery (Surgery-ART Hybrid Therapy) in Infertile Women with Diminished Ovarian Reserve and Uterine Myomas or Ovarian Endometriomas.

J Minim Invasive Gynecol 2019 Nov - Dec;26(7):1369-1375. Epub 2019 Feb 19.

Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan (Drs. Kuroda, Nakagawa, and Sugiyama).

Study Objective: To analyze the clinical outcomes of and predictive factors for the therapeutic effect of combination treatment of preoperative embryo cryopreservation and endoscopic surgery (surgery-assisted reproductive technology [ART] hybrid therapy) in infertile women with diminished ovarian reserve (DOR) with uterine fibroids and/or ovarian endometriomas.

Design: Retrospective cohort study.

Setting: Data from all patients who underwent surgery-ART hybrid therapy at Juntendo University Hospital and Sugiyama Clinic between 2014 and 2016 were analyzed retrospectively. We compared women who experienced live birth (success group) and implantation failure or miscarriage (failure group) after surgery-ART hybrid therapy and evaluate the predictive factors for live birth.

Patients: A total of 39 infertile women underwent surgery-ART hybrid therapy with 86 embryo transfer cycles.

Interventions: All women underwent ART treatment for embryo cryopreservation preoperatively, reproductive surgery, and warmed embryo transfer after the postoperative contraceptive interval (surgery-ART hybrid therapy) for women with DOR (anti-Müllerian hormone <1.0 ng/mL) and/or advanced reproductive age (>40 years) with uterine myomas and/or ovarian endometriomas who required surgery.

Results: Among 39 women underwent surgery-ART hybrid therapy, 1 woman acquired no embryo after oocyte retrieval trials and abandoned efforts to conceive, 14 experienced childbirth (success group) and 24 (63.2%) experienced implantation failure or miscarriage (failure group) after surgery-ART hybrid therapy. The median patient age was 40 years (interquartile range [IQR], 38-41 years) in the success group and 41.5 years (IQR, 41-42 years) in the failure group (p = .032). The respective serum anti-Müllerian hormone levels were 2.5 ng/mL (range, 0.1-8.6 ng/mL) and 1.3 ng/mL (range, 0.1-4.2 ng/mL) (p = .396), and the respective numbers of preoperative frozen were 5.0 (range, 4.0-6.0) and 2.0 (range, 1.0-3.0) (p < .001). There were no significant differences in surgical findings of myomas and endometriosis between the 2 groups. Compared with the 24 women who experienced hybrid therapy failure, the 14 who underwent successful surgery-ART hybrid therapy were significantly younger and had a greater number of cryopreserved embryos.

Conclusion: Successful surgery-ART hybrid therapy requires a sufficient preoperative age-specific number of frozen embryos, establishment of ART treatment with stable pregnancy outcomes and skillful reproductive surgery, and a strong desire of the patient and doctor for pregnancy.
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http://dx.doi.org/10.1016/j.jmig.2019.02.008DOI Listing
May 2020

Pump-probe measurement of metastable state lifetime reduced by cooperative upconversion in a high-concentration erbium-doped fiber.

Appl Opt 2018 Oct;57(30):8819-8823

We report measurements of the metastable state lifetime in a high-concentration erbium-doped fiber. We use a single-wavelength pump-probe technique that allows us to measure the average lifetime over the entire fiber length. A reduction in the lifetime of approximately 20% caused by a cooperative upconversion effect is clearly observed when the input power is increased up to 10 mW. The input power dependence of the lifetime is analyzed using a simple model. The cooperative upconversion coefficient is determined based on this analysis.
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http://dx.doi.org/10.1364/AO.57.008819DOI Listing
October 2018

Reciprocal changes of H3K27ac and H3K27me3 at the promoter regions of the critical genes for endometrial decidualization.

Epigenomics 2018 09 13;10(9):1243-1257. Epub 2018 Sep 13.

Department of Maternal-Fetal Biology, National Research Institute for Child Health & Development, Tokyo 157-8535, Japan.

Aim: Decidualization is essential for embryo implantation and placental development. We aimed to obtain transcriptome and epigenome profiles for primary endometrial stromal cells (ESCs) and in vitro decidualized cells.

Materials & Methods: ESCs isolated from human endometrial tissues remained untreated (D0), or decidualized for 4 days (D4) and 8 days (D8) in the presence of 8-bromo-cAMP and progesterone.

Results: Among the epigenetic modifications examined (DNA methylation, H3K27ac, H3K9me3 and H3K27me3), the H3K27ac patterns changed most dramatically, with a moderate correlation with gene expression changes, upon decidualization. Subsets of up- and down-regulated genes upon decidualization were associated with reciprocal changes of H3K27ac and H3K27me3 modifications at their promoter region, and were enriched with genes essential for decidualization such as WNT4, ZBTB16, PROK1 and GREB1.

Conclusion: Our dataset is useful to further elucidate the molecular mechanisms underlying decidualization.
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http://dx.doi.org/10.2217/epi-2018-0006DOI Listing
September 2018

Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women.

Nutrients 2018 Jul 13;10(7). Epub 2018 Jul 13.

Department of Obstetrics and Gynecology, Juntendo University, Faculty of Medicine, Tokyo 1138421, Japan.

Vitamin D (VD) deficiency is associated with reproductive failure. However, the relationship between VD and maternal immunity remains unclear. We investigated the clinical efficacy of VD in maternal T-helper (Th) cytokines in 276 infertile women and examined for Th1 and Th2 cells based on the deficient, insufficient, and sufficient serum 25-hydroxyvitamin D3 (25[OH]VD) levels (<12, 12⁻30, and >30 ng/mL, respectively). Most infertile women had a low-level of VD (87.3%). Immunological tests of pre-/post-VD supplementation were performed in patients who were deficient and insufficient in VD. Of 23 patients, 11 (47.8%) exhibited sufficient VD levels after supplementation. Th1/Th2 cell ratio in patients with insufficient VD was significantly decreased after supplementation ( = 0.004). After supplementation, serum 25(OH)VD levels of the patients: 11 in the sufficient group showed significant decreases in Th1 cell level and Th1/Th2 cell ratio ( = 0.032 and 0.010, respectively), whereas no significant differences in Th1/Th2 cell ratio were recognized in the insufficient group. Furthermore, mid-luteal endometrial biopsies ( = 18) were processed for primary cultures and measured interferon [IFN]-γ and interleukin [IL]-4 in condition media. Decidualizing cultures with 1,25-dihydroxvitamin D3 (1,25[OH]₂VD) decreased IFN-γ. Sufficient VD supplementation in women with insufficient VD may optimize maternal T-helper cytokines during pregnancy via rebalancing the Th1/Th2 cell ratio.
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http://dx.doi.org/10.3390/nu10070902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073370PMC
July 2018

Infertility treatment strategy involving combined freeze-all embryos and single vitrified-warmed embryo transfer during hormonal replacement cycle for in vitro fertilization of women with hypogonadotropic hypogonadism.

J Obstet Gynaecol Res 2018 May 13;44(5):922-928. Epub 2018 Feb 13.

Department of Obstetrics & Gynaecology, Juntendo University, Tokyo, Japan.

Aim: Hypogonadotropic hypogonadism (HH) is a condition caused by the deficient secretion of pituitary gonadotropins, leading to diminished ovarian function. Several studies of in vitro fertilization (IVF) in women with HH revealed acceptable clinical pregnancy outcomes but high multiple pregnancy rates after multiple fresh embryo transfer (ET). The purpose of this study was to analyze the outcomes of combined freeze-all embryos and single vitrified-warmed ET in women with HH.

Methods: Of 91 infertile women with HH (basal luteinizing hormone and follicle-stimulating hormone levels <2.0 mIU/mL), we excluded patients aged ≥40 years (n = 2) and women who preferred fresh ET (n = 10). Seventy-nine women underwent 117 oocyte retrieval cycles and 135 vitrified-warmed ET during hormone replacement (HR) cycles from 2008 to 2014 at the Kato Ladies Clinic and Juntendo University Hospital.

Results: In 26 single cleavage ET cycles, the rates of clinical pregnancy and live birth were 34.6% (9/26 ET) and 26.9% (7/26 ET), respectively. Regarding the outcomes after single vitrified-warmed blastocyst transfer, clinical pregnancy and live birth rates were 65.1% (71/109 ET) and 50.5% (55/109 ET), respectively. Multiple conceptions and ovarian hyperstimulation syndrome did not occur in any of the women with HH.

Conclusion: Our results demonstrated that IVF followed by single vitrified-warmed ET in adjusted endocrine milieu during the HR cycle is an effective fertility treatment for women with HH and decreases the incidence of complications, including multiple conceptions.
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http://dx.doi.org/10.1111/jog.13597DOI Listing
May 2018

Levothyroxine supplementation improves serum anti-Müllerian hormone levels in infertile patients with Hashimoto's thyroiditis.

J Obstet Gynaecol Res 2018 Apr 3;44(4):739-746. Epub 2018 Jan 3.

Shinbashi Yume Clinic, Tokyo, Japan.

Aim: Thyroid dysfunction and autoimmunity are associated with an adverse effect on fertility. An aberrant high thyroid stimulating hormone level is associated with diminished ovarian reserve in women of reproductive age; however, the utility of levothyroxine (LT4) replacement for infertile patients with subclinical hypothyroidism is still under discussion. The aim of this study was to investigate whether LT4 supplementation for infertile patients with subclinical hypothyroidism improves impaired ovarian function.

Methods: We measured levels of serum thyroid-related hormones and a biomarker of ovarian function, anti-Müllerian hormone (AMH) in infertile women from 2014 to 2015. Out of a consecutive 1431 infertile patients, 311 patients with an elevated thyroid stimulating hormone level (≥ 2.5 μIU/mL) underwent detailed thyroid examinations, including blood tests of thyroid antibodies. We recruited 174 infertile patients, excluding patients with factors impacting ovarian and thyroid function. We evaluated alterations in AMH and thyroid related hormone levels during LT4 supplementation and infertility treatment with assisted reproductive technology.

Results: After LT4 supplementation, no significant change in the average AMH level was detected overall. However, the AMH level in 35 patients with Hashimoto's disease increased significantly after treatment (1 month 1.3 ± 0.5 fold, P = 0.007; 3 months 1.3 ± 0.4 fold, P = 0.040). The AMH level in patients with thyroglobulin antibody-positive and thyroid peroxidase antibody-negative also significantly increased after LT4 treatment (1 and 3 months 1.5 fold; P = 0.023).

Conclusion: In the patients with Hashimoto's disease, preconception LT4 treatment may relieve adverse effects, including autoimmune antibodies, and support follicular development.
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http://dx.doi.org/10.1111/jog.13554DOI Listing
April 2018

After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby.

Reprod Med Biol 2017 07 21;16(3):297-301. Epub 2017 Jun 21.

Department of Maternal-Fetal Biology National Center for Child Health and Development Tokyo Japan.

Aim: An immune etiology for idiopathic recurrent miscarriage is an important issue because a fetus is allogenetically different from the mother. Type 1 T helper (Th1) and Type 2 (Th2) cells have important functions in immune responses and there is a general agreement that pregnancy is associated with Th2 cell dominance. The purpose of this case report is to establish the effectiveness of an immunosuppressive treatment for a patient who had 11 consecutive miscarriages despite several treatments, such as anticoagulation, that showed elevated Th1/Th2 cell ratios.

Methods: This patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks' gestation. The Th1/Th2 cell ratio was evaluated after the 12th conception and she received an immunosuppressive treatment (tacrolimus; 1 mg/d).

Results: The Th1/Th2 cell ratio was elevated after the 12th conception, but the patient miscarried, with a normal karyotype of chorionic villi despite the immunosuppressive treatment. After the 13th conception, she began receiving treatment with 2 mg/d of tacrolimus at 4 weeks' gestation, which was continued until delivery.

Conclusion: For recurrent miscarriage cases that show an elevated Th1/Th2 cell ratio after achieving pregnancy, immunosuppressive treatment with tacrolimus could be effective.
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http://dx.doi.org/10.1002/rmb2.12040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715883PMC
July 2017

Immunosuppressive treatment using tacrolimus promotes pregnancy outcome in infertile women with repeated implantation failures.

Am J Reprod Immunol 2017 Sep 3;78(3). Epub 2017 May 3.

Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan.

Problem: We aim to investigate whether the peripheral blood T helper (Th) 1 cell level could predict pregnancy outcome in patients who have experienced repeated implantation failure (RIF, three or more) after ART cycles.

Method Of Study: This is a prospective cohort study of total 124 women with RIF who showed elevated Th1/Th2 (CD4 IFN-γ /CD4 IL-4 ) cell ratios (≥10.3) and received tacrolimus at Sugiyama Clinic between November 2011 and July 2016. Patients were divided into three groups as per Th1 cell levels: Th1 level of <22.8 as Low; 22.8 to <28.8 as Middle, and 28.8 or greater as High group. The study patients received daily dose of tacrolimus 1-3 mg based on initial Th1/Th2 cell ratio.

Results: The clinical pregnancy rates of Low, Middle, and High groups were 48.8%, 43.9%, and 33.3%, respectively (P=NS), with tacrolimus treatment. The ongoing pregnancy/delivery rate of Low group (46.3%) was significantly higher than that of High group (21.4%, P<.05). Middle group (34.3%) had higher success rate than High group, albeit without statistical significant.

Conclusion: We confirm our previous report that Th1/Th2 ratio can predict ART outcomes in patients with RIF and immunosuppressant treatment with tacrolimus, and peripheral blood Th1 cell levels were negatively correlated with pregnancy outcome.
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http://dx.doi.org/10.1111/aji.12682DOI Listing
September 2017

The establishment of appropriate methods for egg-activation by human PLCZ1 RNA injection into human oocyte.

Cell Calcium 2017 07 6;65:22-30. Epub 2017 Mar 6.

Saint Mother Obstetrics and Gynecology Clinic, Institute for ART, Fukuoka 807-0825, Japan.

Phospholipase C-zeta (PLCZ1), a strong candidate of egg-activating sperm factor, can induce Ca oscillations and cause egg activation. For the application of PLCZ1 to clinical use, we examined the pattern of Ca responses and developmental rate by comparing PLCZ1 RNA injection methods with the other current methods, such as cytosolic aspiration, electrical stimulation and ionomycin treatment in human oocytes. We found that the pattern of Ca oscillations after PLCZ1 RNA injection exhibited similar characteristics to that after ICSI treatment. We also determined the optimal concentration of human PLCZ1 RNA to activate the human oocytes. Our findings suggest that human PLCZ1 RNA is a better therapeutic agent to rescue human oocytes from failed activation, leading to normal and efficient development.
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http://dx.doi.org/10.1016/j.ceca.2017.03.002DOI Listing
July 2017
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