Shimizu, Ryoko



School of Medicine, Center for Preventive Medicine (Shinanomachi)


Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)

External Links

Career 【 Display / hide

  • 1998.04

    慶應義塾大学病院 内科研修医

  • 2002.04

    慶應義塾大学病院 腎臓内分泌代謝内科専修医

  • 2003.05

    慶應義塾大学医学部 腎臓内分泌代謝内科助手

  • 2004.06

    慶應義塾大学病院 救急部専修医

  • 2005.06

    慶應義塾大学医学部 救急医学助手

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Academic Background 【 Display / hide

  • 1998.03

    Keio University, Faculty of Medicine

    University, Graduated

  • 2002.03

    Keio University, Graduate School, Division of Medicine, Internal Medicine

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • M.D., Ph.D., Keio University, Coursework, 2002.03

Licenses and Qualifications 【 Display / hide

  • 医師免許, 1998.03


Research Areas 【 Display / hide

  • Life Science / Cardiology (Circulatory Organs Internal Medicine)

  • Life Science / Nephrology (Kidney Internal Medicine)

  • Life Science / Metabolism and endocrinology

Research Keywords 【 Display / hide

  • extracellular matrix

Research Themes 【 Display / hide

  • the role of extracellular matrix in the development of insulin resistance, 


  • the role of extracellular matrix and inflammation in the pathogenesis of aortic dissection, 


  • 腎障害、血管障害における細胞外基質の病態生理, 


     View Summary



Books 【 Display / hide

  • 実践臨床生殖免疫学

    Shimizu-Hirota Ryoko, 中外医学社, 2018.05

    Scope: 分娩後の子宮機能回復

Papers 【 Display / hide

  • Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor

    Matsuo M., Hirota Y., Fukui Y., Fujita H., Saito-Fujita T., Kaku T., Gebril M., Hirata T., Akaeda S., Hiraoka T., Tanaka T., Haraguchi H., Saito-Kanatani M., Shimizu-Hirota R., Takeda N., Fujii T., Osuga Y.

    Endocrinology (Endocrinology)  161 ( 2 )  2020.02

     View Summary

    © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 μg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 μg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.

  • Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

    Haraguchi H., Hirota Y., Saito-Fujita T., Tanaka T., Shimizu-Hirota R., Harada M., Akaeda S., Hiraoka T., Matsuo M., Matsumoto L., Hirata T., Koga K., Wada-Hiraike O., Fujii T., Osuga Y.

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB journal : official publication of the Federation of American Societies for Experimental Biology)  33 ( 2 ) 2610 - 2620 2019.02

    ISSN  08926638

     View Summary

    Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [ Mdm2-loxP/ progesterone receptor ( Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells ( Mdm2-loxP/ p53-loxP/ Pgr-Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells ( Mdm2-loxP/ anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.-Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., Osuga, Y. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.

  • Negative effect of fatty liver on visualization of pancreatic cystic lesions at screening transabdominal ultrasonography

    Kashiwagi K., Seino T., Makino K., Shimizu-Hirota R., Takayama M., Yoshida T., Iwasaki E., Sugino Y., Inoue N., Iwao Y., Kanai T.

    Journal of Evaluation in Clinical Practice (Journal of Evaluation in Clinical Practice)  26 ( 1 ) 256 - 261 2019

    ISSN  13561294

     View Summary

    © 2019 John Wiley & Sons, Ltd. Rationale, aims, and objectives: The aim of this observational study is to identify factors by which some pancreatic cystic lesions (PCLs) were undetectable at transabdominal ultrasonography (TAUS), using magnetic resonance imaging (MRI) as reference standard. Methods: The database for 781 consecutive subjects who underwent a health checkup including fat computed tomography and upper abdominal MRI as option was searched. The presence of fatty liver and fatty pancreas was diagnosed by TAUS, and atrophic pancreas was determined by reevaluating the image of the pancreas in the chest computed tomography for screening. Subjects with PCL detected and those undetected at TAUS were statistically compared in clinical characteristics. Results: The prevalence of PCL detected at MRI was 17.8% in the general population. Multivariate logistic regression analysis showed that fatty liver, body mass index, and the size of PCL were significantly associated with the factors influencing the visualization of PCL at TAUS (odds ratio [OR]: 0.337, 95% confidence interval [CI]: 0.154-0.734, P = 0.006; OR: 0.852, 95% CI: 0.737-0.985, P = 0.030; OR:1.120, 95% CI: 1.045-1.200, P =.001). Thirty-six PCLs (64.3%) in a total of 56 PCLs were undermeasured by TAUS. Additionally, nine (56%) out of 16 PCLs (≥ 15 mm) were undermeasured by 5 mm or more by TAUS, although a significantly higher detection rate was observed for PCLs (≥ 15 mm) in comparison with that for PCLs (< 15 mm) (80% vs 33.6%, P =.000). Conclusions: It should be noted that coexisting fatty liver may lower the detection of PCL, and its size may be underestimated by TAUS.

  • HIF2 alpha in the uterine stroma permits embryo invasion and luminal epithelium detachment

    Matsumoto, Leona, Hirota, Yasushi, Saito-Fujita, Tomoko, Takeda, Norihiko, Tanaka, Tomoki, Hiraoka, Takehiro, Akaeda, Shun, Fujita, Hidetoshi, Shimizu-Hirota, Ryoko, Igaue, Shota, Matsuo, Mitsunori, Haraguchi, Hirofumi, Saito-Kanatani, Mayuko, Fujii, Tomoyuki, Osuga, Yutaka

    JOURNAL OF CLINICAL INVESTIGATION (Journal of Clinical Investigation)  128 ( 7 ) 3186 - 3197 2018.07

    Research paper (scientific journal),  ISSN  0021-9738

     View Summary

    © 2018 American Society for Clinical Investigation. All rights reserved. Although it has been reported that hypoxia inducible factor 2 a (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P 4 ) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2a in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2a regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2a allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

  • F4/80(+) Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus

    Egashira, Mahiro, Hirota, Yasushi, Shimizu-Hirota, Ryoko, Saito-Fujita, Tomoko, Haraguchi, Hirofumi, Matsumoto, Leona, Matsuo, Mitsunori, Hiraoka, Takehiro, Tanaka, Tomoki, Akaeda, Shun, Takehisa, Chiaki, Saito-Kanatani, Mayuko, Maeda, Kei-ichiro, Fujii, Tomoyuki, Osuga, Yutaka

    ENDOCRINOLOGY 158 ( 7 ) 2344 - 2353 2017.07

    Research paper (scientific journal),  ISSN  0013-7227

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Papers, etc., Registered in KOARA 【 Display / hide

Presentations 【 Display / hide

  • F4/80陽性マクロファージによるマウス分娩後子宮の老化細胞除去と次回妊娠に及ぼす影響

    Shimizu-Hirota Ryoko

    2017年生命科学系合同年次大会 (神戸) , 


    Oral presentation (general), 日本分子生物学会

  • 好中球由来MMP9が急性大動脈解離を誘発する

    Shimizu-Hirota Ryoko

    日本内分泌学会 (東京) , 


    Oral presentation (general), 日本内分泌学会

  • 好中球由来MMP9を介した大動脈解離の発症機構

    Shimizu-Hirota Ryoko

    日本高血圧学会 (大阪) , 


    Oral presentation (general), 日本高血圧学会

  • MMPを介した大動脈解離の発症機構

    Shimizu-Hirota Ryoko

    日本血管生物医学会 (大阪) , 


    Oral presentation (invited, special), 日本血管生物医学会

  • 好中球由来MMPを介した大動脈解離の発症機構

    Shimizu-Hirota Ryoko

    日本病態プロテアーゼ学会 (大阪) , 


    Oral presentation (general), 日本病態プロテアーゼ学会

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • the role of Hippo pathway in the pathogenesis of acute aortic dissection


    基盤研究(C), Principal investigator

  • effect of lysyl oxidase-induced matrix rigidity change on fat browning


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • 血管細胞老化による急性大動脈解離の発症機構の解明


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Awards 【 Display / hide

  • 循環器学研究振興財団研究奨励金

    Shimizu-Hirota Ryoko, 2005.01, 循環器学研究振興財団

    Type of Award: Award from publisher, newspaper, foundation, etc.

  • 第30回日本心臓財団研究奨励金

    Shimizu-Hirota Ryoko, 2004.11, 日本心臓財団

    Type of Award: Award from publisher, newspaper, foundation, etc.

  • 東京高血圧研究会優秀演題奨励賞

    Shimizu-Hirota Ryoko, 2004.09, 東京高血圧研究会

    Type of Award: Award from Japanese society, conference, symposium, etc.

  • 慶應義塾大学医学部学術振興基金

    Shimizu-Hirota Ryoko, 2004.06, 慶應義塾大学医学部

    Type of Award: Keio commendation etc.

  • 慶應義塾大学医学部学術振興基金

    Shimizu-Hirota Ryoko, 2003.06, 慶應義塾大学医学部

    Type of Award: Keio commendation etc.


Courses Previously Taught 【 Display / hide

  • 予防医学 症例検討




Memberships in Academic Societies 【 Display / hide

  • 日本高血圧学会

  • 日本内科学会

  • 日本内分泌学会

  • 日本人間ドック学会


Committee Experiences 【 Display / hide


    会員, 日本内分泌学会


    会員, 日本腎臓学会


    会員, 日本高血圧学会


    会員, 日本透析学会


    会員, 日本内科学会

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