PMID- 28137855 OWN - NLM STAT- MEDLINE DCOM- 20180410 LR - 20181113 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 114 IP - 9 DP - 2017 Feb 28 TI - AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. PG - E1688-E1697 LID - 10.1073/pnas.1620729114 [doi] AB - The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Mullerian inhibiting substance (MIS) (or anti-Mullerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy. FAU - Kano, Motohiro AU - Kano M AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Sosulski, Amanda E AU - Sosulski AE AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Zhang, LiHua AU - Zhang L AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Saatcioglu, Hatice D AU - Saatcioglu HD AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Wang, Dan AU - Wang D AD - Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655. FAU - Nagykery, Nicholas AU - Nagykery N AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Sabatini, Mary E AU - Sabatini ME AD - Department of Obstetrics and Gynecology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114. FAU - Gao, Guangping AU - Gao G AD - Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655. FAU - Donahoe, Patricia K AU - Donahoe PK AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; DPEPIN@mgh.harvard.edu pdonahoe@partners.org. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Pepin, David AU - Pepin D AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; DPEPIN@mgh.harvard.edu pdonahoe@partners.org. AD - Department of Surgery, Harvard Medical School, Boston, MA 02115. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170130 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antineoplastic Agents) RN - 0 (Contraceptive Agents) RN - 80497-65-0 (Anti-Mullerian Hormone) SB - IM CIN - Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2101-2102. PMID: 28213496 MH - Animals MH - Anti-Mullerian Hormone/*pharmacology MH - Antineoplastic Agents/*adverse effects MH - Contraception/methods MH - Contraceptive Agents/*pharmacology MH - Dependovirus/metabolism MH - Female MH - Granulosa Cells/drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Ovarian Follicle/*drug effects MH - Ovarian Reserve/*drug effects MH - Primary Ovarian Insufficiency/prevention & control MH - Reproduction/drug effects PMC - PMC5338508 OTO - NOTNLM OT - AAV9 OT - AMH OT - MIS OT - contraceptive OT - oncofertility COIS- The authors declare no conflict of interest. EDAT- 2017/02/01 06:00 MHDA- 2018/04/11 06:00 PMCR- 2017/01/30 CRDT- 2017/02/01 06:00 PHST- 2017/02/01 06:00 [pubmed] PHST- 2018/04/11 06:00 [medline] PHST- 2017/02/01 06:00 [entrez] PHST- 2017/01/30 00:00 [pmc-release] AID - 1620729114 [pii] AID - 201620729 [pii] AID - 10.1073/pnas.1620729114 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1688-E1697. doi: 10.1073/pnas.1620729114. Epub 2017 Jan 30.