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Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1688-E1697. doi: 10.1073/pnas.1620729114. Epub 2017 Jan 30.

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy.

Author information

1
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114.
2
Department of Surgery, Harvard Medical School, Boston, MA 02115.
3
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655.
4
Department of Obstetrics and Gynecology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
5
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; DPEPIN@mgh.harvard.edu pdonahoe@partners.org.

Abstract

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. Müllerian inhibiting substance (MIS) (or anti-Müllerian 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.

KEYWORDS:

AAV9; AMH; MIS; contraceptive; oncofertility

PMID:
28137855
PMCID:
PMC5338508
DOI:
10.1073/pnas.1620729114
[Indexed for MEDLINE]
Free PMC Article

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