Aromatase induces ovulation via a reduction of follicular androgen and its application for infertility treatment

• Project/Area Number: 25253092
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Chiba University
• Principal Investigator: SHOZU Makio 千葉大学, 大学院医学研究院, 教授 (30226302)
• Co-Investigator(Kenkyū-buntansha): 幡野 雅彦 千葉大学, 大学院医学研究院, 教授 (20208523) ; 石川 博士 千葉大学, 大学院医学研究院, 助教 (70553973) ; 花岡 英紀 千葉大学, 医学部附属病院, 教授 (80361426) ; 碓井 宏和 千葉大学, 大学院医学研究院, 講師 (90375634)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥38,870,000 (Direct Cost: ¥29,900,000、Indirect Cost: ¥8,970,000); Fiscal Year 2015: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2014: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2013: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
• Keywords: 生殖医学 / アロマターゼ / 産婦人科学

Outline of Final Research Achievements

We tested the hypothesis that aromatase trigger follicular rupture (ovulation) via a reduction of local androgen levels and tried to develop new treatment based on the theory. We developed in vitro PCOS model in which low dose hCG causes ovulatory response low. In this model, Cyp17a1 inhibitor which restored ovulatory responses of the model as well as oocyte maturation. The human oocytes were recovered from small non-dominant follicles of infertile women who underwent IVF-ET therapy. At least one forth of these oocytes were metaphase II and competent for live birth. This indicates that al least a part of the non-dominant follicles maintains oocyte competency until mid-cycle ovulation despite the high androgen status. Needle aspiration of those follicle and following IVF-ET may be an alternate therapy for those anovulatory women without gonadotropins-induced ovulation.

Research Products

• [Journal Article] Mature cystic teratomas arise from meiotic oocytes, but not from pre-meiotic oogonia. (2016)
  • Author(s): Kaku H, Usui H, Qu J, Shozu M.
  • Journal Title: Genes Chromosomes Cancer. Volume: 55(4) Issue: 4 Pages: 355-64
  • DOI: 10.1002/gcc.22339
  • Peer Reviewed
• [Journal Article] Nondominant small follicles are a promising source of mature oocytes in modified natural cycle in vitro fertilization and embryo transfer (2016)
  • Author(s): Teramoto S, Osada H, Sato Y, Shozu M.
  • Journal Title: Fertil Steril Volume: -
  • Peer Reviewed
• [Journal Article] Elevated serum progesterone levels in postmenopausal women with mucinous ovarian tumors (2016)
  • Author(s): Matsuoka A, Tate S, Nishikimi K, Ishikawa H, Shozu M
  • Journal Title: Menopause Volume: -
  • Peer Reviewed
• [Journal Article] Nonobese diabetic/severe combined immunodeficient murine xenograft model for human uterine leiomyoma. (2014)
  • Author(s): Wang G, Ishikawa H, Sone K, Kobayashi T, Kim JJ, Kurita T, Shozu M.
  • Journal Title: Fertility and Sterility Volume: 印刷中 Issue: 5 Pages: 1485-1492.e3
  • DOI: 10.1016/j.fertnstert.2014.01.054
  • Peer Reviewed
• [Journal Article] Lack of genomic rearrangements involving the aromatase gene CYP19A1 in breast cancer. (2014)
  • Author(s): Fukami M*, Suzuki J, Nakabayashi K, Tsunashima R, Ogata T, Shozu M, Noguchi S
  • Journal Title: Breast Cancer Volume: 21 (3) Issue: 3 Pages: 382-385
  • DOI: 10.1007/s12282-013-0471-5
  • Peer Reviewed
• [Journal Article] Review: Understanding the pathological manifestations of aromatase excess syndrome: lessons for the clinic. (2014)
  • Author(s): M. Shozu, M. Fukami and T. Ogata
  • Journal Title: Expert Rev. Endocrinol. Metab. Volume: 9 Issue: 4 Pages: 397-409
  • DOI: 10.1586/17446651.2014.926810
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre-or peri-pubertal onset gynecomastia (2014)
  • Author(s): Fukami M, Miyado M, Nagasaki K, Shozu M, Ogata T.
  • Journal Title: Pediatr Endocrinol Rev. Volume: 11(3) Pages: 298-305
  • Peer Reviewed
• [Journal Article] Aromatase excess syndrome in a family with upstream deletion of CYP19A1 (2013)
  • Author(s): Shihara D, Miyado M, Nakabayashi K, Shozu M, Nagasaki K, Ogata T, Fukami M*
  • Journal Title: Clin Endocrinol, Volume: Epub ahead of print Issue: 2 Pages: 314-316
  • DOI: 10.1111/cen.12329
  • Peer Reviewed
• [Journal Article] Lifestyle and osteoporosis in middle-aged and elderly women: Chiba bone survey (2013)
  • Author(s): Ichiro Tatsuno, Takashi Terano, Mitsugu Nakamura, Kiminori Suzuki, Kazuko Kubota, Jyunichi Yamaguchi, Tomohiko Yoshida, Sawako Suzuki, Tomaki Tanaka and Makio Shozu
  • Journal Title: Endocrine Journal Volume: 60 Issue: 5 Pages: 643-650
  • DOI: 10.1507/endocrj.EJ12-0368
  • NAID: 10031184532
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma (2013)
  • Author(s): Yamamoto N, Kinoshita T, Nohata N, Itesako T, Yoshino H, Enokida H, Nakagawa M, Shozu M, and Seki N
  • Journal Title: International journal of oncology Volume: 42 Issue: 5 Pages: 1523-1532
  • DOI: 10.3892/ijo.2013.1851
  • Peer Reviewed
• [Journal Article] Efficient subtractive cloning of genes activated by lipopolysaccharide and interferon γ in primary-cultured cortical cells of newborn mice. (2013)
  • Author(s): Miyauchi, O., Iwase, K., Itoh, K., Kato, M., Seki, N., Braissant, O., Bachmann, C., Shozu, M., Sekiya, S., Osada, H., and Takiguchi, M.
  • Journal Title: PLoS ONE Volume: 8 Issue: 11 Pages: e79236-e79236
  • DOI: 10.1371/journal.pone.0079236
  • Peer Reviewed
• [Journal Article] Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression. (2013)
  • Author(s): Fukami M*, Tsuchiya T, Vollbach H, Brown KA, Abe S, Ohtsu S, Wabitsch M, Gurger H, Sompson ER, Emezawa A, Nakabayashi K, Bulun SE, Shozu M, Ogata T
  • Journal Title: J Clin Endocrinol Metab Volume: 98 Issue: 12 Pages: E2013-E2021
  • DOI: 10.1210/jc.2013-2520
  • Peer Reviewed
• [Journal Article] Tumor-suppressive microRNA-29a inhibits cancer cell migration and invasion via targeting HSP47 in cervical squamous cell carcinoma. (2013)
  • Author(s): Yamamoto N, Kinoshita T, Nohata N, Yoshino H, Itesako T, Fujimura L, Mitsuhashi A, Usui H, Enokida H, Nakagawa M, Shozu M, and Seki N
  • Journal Title: Int J Oncol Volume: 43 Issue: 6 Pages: 1855-1863
  • DOI: 10.3892/ijo.2013.2145
  • Peer Reviewed
• [Journal Article] 女性のライフステージとエストロゲン－アロマターゼとの関わり－ (2013)
  • Author(s): 生水真紀夫
  • Journal Title: 日本女性医学学会雑誌 Volume: 20(3) Pages: 432-438
• [Journal Article] ホルモン療法実践マニュアル 各論Ⅱ．腫瘍分野12.アロマターゼ阻害薬と婦人科がん (2013)
  • Author(s): 三橋暁、生水真紀夫
  • Journal Title: 産科と婦人科増刊号 Volume: No.80 Suppl. Pages: 169-173
• [Journal Article] 子宮体がん診療アップデート ９．治療のトピックス 子宮体がんの妊孕性温存療法 (2013)
  • Author(s): 三橋暁、生水真紀夫
  • Journal Title: 臨床婦人科産科 Volume: 67(5) Pages: 498-504
• [Journal Article] 特集：ホルモン依存性悪性腫瘍－特徴と対処を考える－子宮体がん：子宮体がんでの妊孕性温存療法の新たな展開 (2013)
  • Author(s): 三橋暁、生水真紀夫
  • Journal Title: 産婦人科の実際 Volume: 62(9) Pages: 1207-1213
• [Journal Article] Organization, Function, and Relationship of Aromatase Promoters (2013)
  • Author(s): Makio Shozu, Tatsuya Kobayashi
  • Journal Title: アンドロロジー学会ニュースレター2013-7； Volume: 7
• [Journal Article] 骨とエストロゲンー思春期の症例に学ぶー (2013)
  • Author(s): 生水真紀夫
  • Journal Title: 埼玉産科婦人科医学会雑誌2 Volume: 43(2) Pages: 167-174
• [Presentation] アロマターゼ阻害剤はマウス体外培養卵法のFshrを増加させる (2015)
  • Author(s): 小林達也、石川博士、石井久美子、生水真紀夫
  • Organizer: 第33回日本受精着床学会総会学術講演会
  • Place of Presentation: TFTホール西館（東京都江東区）
  • Year and Date: 2015-11-26
• [Presentation] Rapid growth and grading system for assisted-hatching blastocysts to predict clinical outcome (2015)
  • Author(s): Segawa T, Teramoto S, Miyauchi O, Omi K, Watanabe Y, Kuroda M, Okubo T, Sozu M
  • Organizer: 31th Annual Meeting of the European Society of Human Reproduction & Embryology(ESHRE)
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2015-06-14
• [Presentation] Expression of luteinizing hormone receptor and concentrations of gonadotropin and sex steroids in non-growing small follicles at oocyte retrieval for in vitro fertilization (2015)
  • Author(s): Ishikawa H, Okubo T, Kobayashi T, Kanetani H, Segawa T, Teramoto S, Shozu M
  • Organizer: IFFS/JSRM International Meeting 2015 in Yokohama
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-26
• [Presentation] 特別講演：アロマターゼの遺伝子異常と疾患 (2015)
  • Author(s): 生水真紀夫
  • Organizer: 第23回東関東臨床ホルモン研究会
  • Place of Presentation: 日本医科大学千葉北総病院（千葉県印西市）
  • Year and Date: 2015-04-18
  • Invited
• [Presentation] 当科における自然周期、卵巣低刺激周期採卵の検討 (2014)
  • Author(s): 石川博士、小林達也、石井久美子、河原井麗正、金谷裕美、藤田真紀、柿沼敏行、生水真紀夫
  • Organizer: 第15回千葉リプロダクション研究会学術講演会
  • Place of Presentation: 三井ガーデンホテル千葉（千葉県千葉市）
  • Year and Date: 2014-10-04
• [Presentation] 自然周期における主席卵胞および小卵胞由来の顆粒膜細胞内LH受容体発現量が卵子成熟度に与える影響 (2014)
  • Author(s): 大久保毅、生水真紀夫、石川博士、瀬川智也、宮内修、林輝明、恩田知幸、松尾涼子、上野剛、寺元章吉
  • Organizer: 第32回日本受精着床学会総会・学術講演会
  • Place of Presentation: ハイアットリージェンシー東京（東京都新宿区）
  • Year and Date: 2014-07-31 – 2014-08-01
• [Presentation] A Case of Nonclassic Congenital Adrenal Hyperplasia in Which Aberrant Serum Progesterone Provides a Diagnostic Clue (2014)
  • Author(s): Kawarai Y, Ishikawa H, Segawa T, Nagano H, Tanaka T, and Shozu M.
  • Organizer: The Endocrine Society's 96th Annual Meeting & EXPO (ENDO 2014）
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] 高アンドロゲン血症をきたした内分泌腫瘍の3例 (2014)
  • Author(s): 河原井麗正、石川博士、柿沼敏行、藤田真紀、金谷裕美、川野みどり、清川貴子、生水真紀夫
  • Organizer: 第66回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-18 – 2014-04-20
• [Presentation] 特別講演：不妊治療とエストロゲンの話題 (2014)
  • Author(s): 生水真紀夫
  • Organizer: 第43回三八地区臨床検査懇話会
  • Place of Presentation: 八戸市立市民病院（青森県八戸市）
  • Year and Date: 2014-02-15
  • Invited
• [Presentation] 子宮内膜症におけるDNMTs、TETs発現からみたエピジェネティック機構の検討 (2014)
  • Author(s): 柿沼敏行、Matthew Dyson、Mary Ellen Pavone、Diana Monsivais、Serdar E Bulun、生水真紀夫
  • Organizer: 第35回日本エンドメトリオーシス学会
  • Place of Presentation: 城山観光ホテル（鹿児島県鹿児島市）
  • Year and Date: 2014-01-25
• [Presentation] 特別講演：エストロゲンとその合成酵素の働き－卵を育て、性を育み、骨を作る (2013)
  • Author(s): 生水真紀夫
  • Organizer: 第16回更年期と加齢のヘルスケア学会神奈川支部
  • Place of Presentation: 三菱重工横浜ビル（神奈川県横浜市）
  • Year and Date: 2013-12-08
  • Invited
• [Presentation] ほ乳類胎盤のアロマターゼ活性はテストステロン濃度と比例する (2013)
  • Author(s): 小林達也、生水真紀夫
  • Organizer: 第18回日本生殖内分泌学会学術集会
  • Place of Presentation: シェーンバッハ・サボー（東京都千代田区）
  • Year and Date: 2013-12-07
• [Presentation] 自然排卵周期における新試薬「iE2」の評価に関する検討 (2013)
  • Author(s): 瀬川智也、寺元章吉、宮内修、渡邉芳明、黒田雅子、篠原一朝、土山哲史、石川博士、 柿沼敏行、生水真紀夫
  • Organizer: 第58回日本生殖医学会学術講演会･総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2013-11-15 – 2013-11-16
• [Presentation] DNA methyltransferase and Ten-Eleven-Translocation Expression in The Human Endometrium: Regulation by Progesterone and Estrogen (2013)
  • Author(s): Toshiyuki Kakinuma, Matthew Dyson, Mary Ellen Pavone, Diana Monsivais, Serdar E Bulun, Makio Shozu
  • Organizer: The 9th Conference of the Pacific Rim Society for Fertility and Sterility
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2013-11-14
• [Presentation] DNA methyltransferase and Ten-Eleven-Translocation Expression in The Human Endometrium (2013)
  • Author(s): Toshiyuki Kakinuma, Matthew Dyson, Mary Ellen Pavone, Diana Monsivais, Serdar E Bulun,Makio Shozu
  • Organizer: 18th World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2013-10-24 – 2013-10-27
• [Presentation] 特別講演：エストロゲンに関する話題 (2013)
  • Author(s): 生水真紀夫
  • Organizer: 平成25年度岩手産科婦人科学会集談会
  • Place of Presentation: ホテルニュー江刺新館イーズ（岩手県奥州市）
  • Year and Date: 2013-10-19
  • Invited
• [Presentation] 特別講演：がん予防薬：メトホルミン (2013)
  • Author(s): 生水真紀夫
  • Organizer: 第27回日本臨床細胞学会関東連合学術集会
  • Place of Presentation: 京葉銀行文化プラザ（千葉県千葉市）
  • Year and Date: 2013-09-07
  • Invited
• [Presentation] 不妊を契機に診断された21水酸化酵素欠損症の1例 (2013)
  • Author(s): 河原井麗正、石川博士、小林達也、金谷裕美、藤田真紀、川野みどり、柿沼敏行、永野秀和、田中知明、瀬川智也、寺元章吉、生水真紀夫
  • Organizer: 第13回千葉内分泌･代謝談話会
  • Place of Presentation: 千葉大学医学部附属病院（千葉県千葉市）
  • Year and Date: 2013-08-29
• [Presentation] 当施設独自に開発した先細採卵針の形状および吸引圧の違いによる小卵胞由来卵子回収成績 (2013)
  • Author(s): 大久保毅、瀬川智也、林輝明、恩田智幸、上野剛、生水真紀夫、寺元章吉
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2013-08-08 – 2013-08-09
• [Presentation] 小卵胞由来MⅡ卵子を採卵する意義に関する検討 (2013)
  • Author(s): 瀬川智也、寺元章吉、宮内修、渡邉芳明、林輝明、大久保毅、恩田智幸、松尾涼子、上野剛、田口智美、水口麻侑子、久手堅舞、篠原一朝、土山哲史、石川博士、柿沼敏行、生水真紀夫
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2013-08-08 – 2013-08-09
• [Presentation] 特別講演：女性のライフスタイルとエストロゲン－アロマターゼの関与－ (2013)
  • Author(s): 生水真紀夫
  • Organizer: 第15回更年期と加齢のヘルスケア学会神奈川支部
  • Place of Presentation: 三菱重工横浜ビル（神奈川県横浜市）
  • Year and Date: 2013-07-28
  • Invited
• [Presentation] Oocyte retrival from collateral follicles improves outcomes of natural or low ovarian stimulus cycle IVF (2013)
  • Author(s): Segawa T, Teramoto S, Miyauchi O, Watanabe Y, Hayashi T, Ohkubo T, Onda N, Ueno T, Tsuchiyama S, Shinohara K, Yelian F, Ishikawa H, Shozu M
  • Organizer: European Society of Human Reproduction and Embryology Annual Meeting
  • Place of Presentation: London, U.K
  • Year and Date: 2013-07-07 – 2013-07-10
• [Presentation] シンポジウム：加齢に伴う卵子の変化 (2013)
  • Author(s): 生水真紀夫
  • Organizer: 第12回生殖バイオロジー東京シンポジウム
  • Place of Presentation: 都市センターホテル（東京都千代田区）
  • Year and Date: 2013-06-23
  • Invited
• [Presentation] 子宮内膜症におけるDNA Methyltransferase（DNMTs)発現に関する検討 (2013)
  • Author(s): 柿沼敏行、生水真紀夫
  • Organizer: 第65回日本産科婦人科学会学術講演会
  • Place of Presentation: ロイトン札幌他（北海道札幌市）
  • Year and Date: 2013-05-10 – 2013-05-12
• [Presentation] 不妊を契機に発見された21水酸化酵素欠損症の1例 (2013)
  • Author(s): 河原井麗正、石川博士、小林達也、金谷裕美、藤田真紀、川野みどり、柿沼敏行、永野秀和、田中知明、瀬川智也、寺元章吉、生水真紀夫
  • Organizer: 第147回関東生殖医学会
  • Place of Presentation: 持田製薬ルークホール（東京都新宿区）
  • Year and Date: 2013-04-20
• [Presentation] 不妊診療における新試薬「iE2」の評価に関する検討 (2013)
  • Author(s): 瀬川智也、寺元章吉、宮内修、渡邉芳明、篠原一朝、土山哲史、石川博士、柿沼敏行、 生水真紀夫
  • Organizer: 第147回関東生殖医学会
  • Place of Presentation: 持田製薬ルークホール（東京都新宿区）
  • Year and Date: 2013-04-20
• [Presentation] Tumor suppressivve microRNA-218 mediated focal adhesion pathways in cervical squamous cell carcinoma (miR-218 as a TS in cervical cancer) (2013)
  • Author(s): Noriko Yamamoto, Takashi Kinosita, Nijiro Nohata, Toshihiko Idesako, Hirofumi Yoshino, Hideki Enokida, Masayuki Nakagawa, Makio Shozu, Naohiko Seki
  • Organizer: American Association for Cancer Research (AACR) Annual Meeting 2013
  • Place of Presentation: Washington, USA
  • Year and Date: 2013-04-06 – 2013-04-10
• [Book] Endometriosis Pathogenesis and Treatment (Harada Ed.) (2014)
  • Author(s): Hiroshi Ishikawa and Makio Shozu
  • Publisher: Springer,