Published papers

＜文献概要＞●がんと診断されてから治療が開始されるまでの限られた時間内に,妊孕性に対するリスクと,適切な妊孕能温存の選択肢について,患者が十分に理解し,医療者とともに協働的意思決定ができるように努めなければならない.●シクロホスファミドを代表とするアルキル化薬剤は卵巣および精巣機能を著しく低下させるリスクがある.●放射線照射は卵巣および精巣機能を低下させるリスクを有し,患者年齢,線量,投与期間などによりリスクの程度は変化する.

＜文献概要＞はじめに　悪性骨・軟部腫瘍は運動器に発生する希少な悪性腫瘍であり,「肉腫」と総称される.骨肉腫,Ewing肉腫などが代表的な疾患であり,若年発症[小児および思春期・若年成人(AYA)世代]が多い.化学療法を含む集学的治療の確立により,高悪性度肉腫の治療成績は改善したが,同時に長期サバイバーの生活の質(QOL)が課題となっている.中でも重要なものが妊孕性の温存である.本稿では,小児・AYA世代の悪性骨・軟部腫瘍患者に対するがん生殖医療について,日本癌治療学会より刊行された『小児,思春期・若年がん患者の妊孕性温存に関する診療ガイドライン2017年版』(本邦妊孕性温存GL)に沿って解説する.

母体加齢と排卵後加齢というふたつのマウスモデルを用いて、卵子の加齢変化に関してテロメラーゼ活性とテロメア長、ミトコンドリアと酸化ストレスに焦点を置き検討した。母体加齢卵におけるTertのmRNA発現は若齢マウス卵に比較して有意に減少し、マイクロアレイの結果とほぼ一致した。排卵後加齢卵におけるTertのmRNA発現は、新鮮卵と比較して有意に減少した。テロメラーゼ酵素活性は若齢卵と比較して母体加齢卵では有意に低下した。酸化ストレスは、若齢卵では、蛍光色素を示さなかったが、母体加齢卵、排卵後加齢卵では有意に増加した。加齢マウス卵のテロメア長は若齢卵に比べて有意に短縮したが、排卵後加齢卵のテロメア長は、若齢卵に比較して有意な変化を認めなかった。

止血制御としての子宮摘出が困難であった帝王切開時の大量出血に対し,子宮動脈塞栓術(Uterine Artery Embolization;以下UAE)が有効であった2例を経験したので,文献的考察も含めて報告する.症例1は44歳,0経妊0経産.子宮内膜症性嚢胞・子宮筋腫合併.体外受精にて妊娠成立し,妊娠23週に超音波断層検査で全前置胎盤と診断.妊娠37週2日,帝王切開術を施行した.術中出血量は約3,000ml.閉創後,弛緩出血によりショック状態となった.内膜症性癒着によるダグラス窩完全閉鎖のため,子宮摘出は困難と判断.UAEを施行し,出血量は減少した.症例2は42歳,4経妊2経産.子宮筋腫核出術.帝王切開術の既往あり.子宮筋腫・子宮腺筋症合併.MRI検査で,胎盤は子宮前壁の子宮腺筋症部位に接して付着.38週2日,帝王切開術を施行.子宮収縮不良により出血が持続し,出血量は約10,000ml.子宮筋腫や子宮腺筋症,強固な腹腔内癒着のため子宮摘出は困難と考え,UAEを施行し,出血量は減少した.子宮摘出困難な分娩後大量出血における緊急UAE施行は,止血制御に有用かつ,母体救命戦略の一助となることが示された.(著者抄録)

子宮角部妊娠は全異所性妊娠の0.6%と稀な疾患であり、いまだ確立された治療法はない。今回子宮鏡検査により子宮角部妊娠を補助診断し、良好な経過を得た症例を経験したので報告する。症例は35歳、1妊0産。無月経5週3日の血中hCG 9930mIU/mL、経腟超音波断層検査で胎嚢を認めず、異所性妊娠疑いにて当院紹介受診。血中hCGの上昇率は緩徐のため異常妊娠と診断した。MRI検査で右子宮角部に胎嚢様構造を認めた。着床部位をより正確に確認し、安全に治療を行うため施行した子宮鏡検査にて右子宮角部に腫瘤性病変を確認した。経腹超音波断層検査併用下に子宮内容除去術を行い、摘出検体の病理組織検査で絨毛組織を認めた。血中hCGは術後すみやかに低下し、術後44日目に陰転化した。子宮鏡検査は着床部位が困難な症例における補助診断および安全な治療遂行に有用であると考える。(著者抄録)

Hermaphroditic invertebrates and plants have a self-recognition system on the cell surface of sperm and eggs, which prevents their self-fusion and enhances non-self-fusion, thereby contributing to genetic variation. However, the system of sperm-egg recognition in mammals is under debate. To address this issue, we explored the role of major histocompatibility complex class I (MHC class I, also known as histocompatibility 2-K(b) or H2-K(b) and H2-D(b) in mice) antigens by analyzing H2-K(b-/-)H2-D(b-/-)β2-microglobulin (β2M)(-/-) triple-knockout (T-KO) male mice with full fertility. T-KO sperm exhibited an increased sperm number in the perivitelline space of wild-type (WT) eggs in vitro. Moreover, T-KO sperm showed multiple fusion with zona pellucida (ZP)-free WT eggs, implying that the ability of polyspermy block for sperm from T-KO males was weakened in WT eggs. When T-KO male mice were intercrossed with WT female mice, the percentage of females in progeny increased. We speculate that WT eggs prefer fusion with T-KO sperm, more specifically X-chromosome-bearing sperm (X sperm), suggesting the presence of preferential (non-random) fertilization in mammals, including humans.

＜文献概要＞女性に対する代表的な妊孕性温存療法には,卵子/受精卵(胚)凍結,卵巣組織凍結が挙げられる。卵子/胚凍結は標準治療の位置づけとして確立しつつある一方,卵巣組織凍結は米国臨床腫瘍学会(ASCO)Clinical Practice Guideline 2018年版ではいまだ実験段階の方法としての位置づけとなっており,有効性・安全性に関する科学的エビデンスの蓄積が求められている。妊孕性温存に向けた実験的な試みとして,in vitro maturation(IVM),卵巣組織凍結における卵胞生存率を高める取り組み,人工卵巣,再生医療による卵子作成などの研究が行われている。本稿では,妊孕性温存療法の実態と限界,今後の展望について解説する。

＜文献概要＞新型コロナウイルス感染症(COVID-19)のパンデミックは,SARS-CoV-2と命名されたコロナウイルスにより引き起こされる。COVID-19パンデミック下においても,女性と男性が子どもを産み,家庭を築く権利をはじめとしたreproductive rightsが尊重され,COVID-19の拡大を防ぐ社会のニーズと調和させるための努力が求められる。本稿では,COVID-19パンデミックにおける日本生殖医学会の取り組みについてまとめる。

Calcium oscillations are rhythmic fluctuations of the intracellular concentration of calcium ions (Ca2+). As Ca2+ evokes various cellular processes, its intracellular concentration is tightly regulated. Ca2+ oscillations control biological events, including neuronal differentiation and proliferation of mesenchymal stem cells. The frequency and pattern of Ca2+ oscillations depend on cell type. Researchers have studied Ca2+ oscillations to better understand how cells communicate and regulate physiological processes. Dysregulation of Ca2+ oscillations causes health problems, such as neurodegenerative disorders. This review discusses the potential functions of Ca2+ oscillations in stem cells.

Aim: To investigate variation in the diagnosis and treatment of chronic endometritis (CE) at the national level in Japan. Methods: We performed a nationwide survey targeting all assisted reproductive technology (ART) facilities across Japan between 2021 and 2022. Diagnostic methods, criteria, and first- and second-line treatment protocols for CE were collected via a questionnaire. Results: Among 616 ART facilities, 437 responded to the survey (response rate: 70.9%) of which 339 (77.6%) implemented diagnosis and treatment of CE. In the diagnosis of CE, 214 (63.1%) facilities used CD138 immunohistochemical staining of endometrial tissue, while hysteroscopy was the most frequently used as an adjunct diagnostic method (241 facilities, 71.1%). The most frequent cutoff value of CD138-positive cells for diagnosing CE was 3–5 cells/20 high-power fields (50%), but 7.9% (17 facilities) and 5.1% (11 facilities) used cutoff values of 1 and 2 cells, respectively. The most common first- and second-line treatment methods were doxycycline (210 facilities, 61.9%) and ciprofloxacin + metronidazole (164 facilities, 48.0%), respectively. Conclusions: There is considerable variation in the number of CD138-positive cells used for diagnosing CE. Establishing unified diagnostic criteria and therapeutic methods for CE is essential to provide standardized medicine for CE at the national level.

This large multi-center retrospective study examined whether artificial oocyte activation (AOA) using Ca2+ ionophore following ICSI improves the live birth rate for couples with previous ICSI cycles of unexplained low fertilization rate. In this large-scale multi-center retrospective study conducted in Japan, data were collected from Keio University and 17 collaborating institutions of the Japanese Institution for Standardizing Assisted Reproductive Technology. Between January 2015 and December 2019, 198 couples were included in this study. Oocytes for both the intervention and control groups were procured from the same pool of couples. Oocytes obtained from ICSI cycles with no or low fertilization rate (<50%) with unknown causes were included in the control (conventional ICSI) group while oocytes procured from ICSI cycles followed by performing AOA were assigned to the intervention (ICSI-AOA) group. Those fertilized with surgically retrieved sperm were excluded. ICSI-AOA efficacy and safety were evaluated by comparing these two groups. Live birth rate was the primary outcome. The ICSI-AOA group (2,920 oocytes) showed a significantly higher live birth per embryo transfer rate (18.0% [57/316]) compared to that of the conventional ICSI group with no or low fertilization rate (1,973 oocytes; 4.7% [4/85]) (odds ratio 4.5, 95% confidence interval 1.6–12.6; P<0.05). A higher live birth rate was observed in younger patients without a history of oocyte retrieval. Miscarriage, preterm delivery, and fetal congenital malformation rates were similar between the two groups. ICSI-AOA may reduce fertilization failure without increasing risks during the perinatal period. AOA may be offered to couples with an ICSI fertilization rate < 50%.

Aims: This study aims to comprehensively examine the employment and practices of embryologists in Japan's assisted reproductive technology (ART) laboratories, focusing on the impact of various factors such as ART cycle numbers, add-ons, and regional differences. Additionally, it seeks to assess the extent to which Japanese ART facilities meet international minimum standards set by the American Society for Reproductive Medicine (ASRM). Methods: A survey was conducted from December 2021 to February 2022 among 621 ART facilities in Japan. The study categorized facilities into five ART cycle groups and compared the number of embryologists across these groups. It also examined the correlation between the number of embryologists, ART cycles, add-ons, and regional differences. Data were analyzed using linear regression and multiple linear regression analyses. Results: The study's findings revealed a significant correlation between the total number of embryologists at each facility and the ART cycles. Notably, there were significant differences in the number of embryologists across all ART cycle categories. Of the 435 facilities, only 44.6% met the ASRM minimum embryologist staffing requirement. The regression analysis further highlighted the significance of ART cycles and preimplantation genetic testing for aneuploidies as factors. Moreover, the number of embryologists stationed at urban facilities was significantly higher than at nonurban facilities, indicating a potential regional disparity. Conclusion: In Japan, it was first found that more than 50% of ART facilities do not have sufficient embryologists in place relative to the number of ART cycles. Furthermore, the add-ons and regional differences affect the placement of embryologists.

Repeated implantation failure is a major cause of infertility among healthy women. Uterine β-catenin (CTNNB1) plays a critical role in implantation. However, the role of embryonic CTNNB1 during implantation remains unclear. We addressed this topic by analyzing mice carrying Ctnnb1-deficient (Ctnnb1Δ/Δ) embryos. Ctnnb1Δ/Δ embryos were produced by intercrossing mice bearing Ctnnb1-deficient eggs and sperms. We found that Ctnnb1Δ/Δ embryos developed to the blastocyst stage; thereafter, they were resorbed, leaving empty decidual capsules. Moreover, leukemia inhibitory factor, a uterine factor essential for implantation, was undetectable in Ctnnb1Δ/Δ blastocysts. Furthermore, CDX2, a transcription factor that determines the fate of trophectoderm cells, was not observed in Ctnnb1Δ/Δ blastocysts. Intrauterine injection with uterine fluids (from control mice) and recombinant mouse leukemia inhibitory factor proteins rescued the uterine response to Ctnnb1Δ/Δ blastocysts. These results suggest that embryonic CTNNB1 is required for the secretion of blastocyst-derived factor(s) that open the implantation window, indicating that the uterine response to implantation can be induced using supplemental materials. Therefore, our results may contribute to the discovery of a similar mechanism in humans, leading to a better understanding of the pathogenesis of repeated implantation failure.

Aims: In anticipation of the future development of assisted reproductive technology (ART) and to smoothly introduce new technology, it is necessary to understand the current staffing status of the medical system and the current state of treatment, as well as the status of in vitro fertilization add-ons, where the need for insurance coverage is currently a matter of debate. Methods: ART facilities in Japan were surveyed (437 valid responses, response rate: 71%). Current staffing status of the medical system, implementation rates of ART, add-on treatments, and medical supplies were investigated. Results: Despite the abundance of embryologists, nurses, and obstetricians and gynecologists in facilities, the majority of facilities lacked counselors, anesthesiologists, and other essential medical professionals. Conventional ovarian stimulation was widely adopted (median 120 [interquartile range 60–300] cycles), followed by mild ovarian simulation (60 [30–200]). Additionally, freeze–thaw embryo transfer cycles (300 [120–750]) were performed more frequently than fresh embryo transfer cycles (30 [30–60]). Among the add-ons, assisted hatching (85.1%), chronic endometritis examination (77.2%) and treatment (76.9%), artificial oocyte activation (67.3%), endometrial receptivity analysis (64.2%), and endometrial microbiome analysis (58.9%) were relatively widely employed. Conclusions: The implementation of frozen–thawed embryo transfer cycles, freeze-all strategies, and add-on treatments have become popular and widely accepted despite the lack of robust evidence regarding their safety and efficacy.

Background: The indications for fertility preservation (FP) have expanded. A few patients who underwent gonadotoxic treatment did not have the opportunity to receive FP, leading to concerns that these patients may develop premature ovarian insufficiency. However, the usefulness of FP in women with reduced ovarian reserve has also been questioned. Progestin-primed ovarian stimulation can improve the controlled ovarian stimulation (COS) protocol, but there is limited data on the efficacy of FP with progestin-primed ovarian stimulation. Methods: We conducted a prospective study of 43 women with cancer or autoimmune diseases before and after gonadotoxic treatment at the reproductive unit of Keio University Hospital, counselled between 1 January 2018 and 31 December 2021. After counselling, informed consent was obtained for FP from 43 patients, with those who underwent gonadotoxic treatment of the primary disease being prioritised. Gonadotropin-releasing hormone analogue or progestin was used to suppress luteinising hormone in COS before or after gonadotoxic treatment. The number of cryopreserved mature oocytes was the primary outcome. Results: Forty-three patients and 67 assisted reproductive technology cycles were included in the analysis. The median age at entry was 32 [inter quartile range (IQR), 29–37] years. All patients in the post-gonadotoxic treatment group had their oocytes frozen. Gonadotoxic treatment resulted in fewer oocytes [median 3 (IQR 1–4); pre-gonadotoxic treatment group: five patients, 13 cycles] vs. median 9 (IQR 5–14; pre-gonadotoxic treatment group: 38 patients, 54 cycles; P < 0.001). Although anti-Müllerian hormone levels were lower in the post-gonadotoxic treatment group (n = 5, 13 cycles, median 0.29 (IQR 0.15–1.04) pg/mL) than in the pre-gonadotoxic treatment group (n = 38, 54 cycles, median 1.89 (IQR 1.15–4.08) pg/mL) (P = 0.004), oocyte maturation rates were higher in the post-gonadotoxic treatment group [median 100 (IQR 77.5–100) %] than in the pre-gonadotoxic group [median 90.3 (IQR 75.0–100) %; P = 0.039]. Five patients in the pre-gonadotoxic treatment group had their cryopreserved embryos thawed, of which three had live births. Conclusions: Oocytes obtained for FP from women with cancer or autoimmune disease for FP are of satisfactory quality, regardless of whether they are obtained post-gonadotoxic treatment or COS protocols.