UMMS Affiliation

Horae Gene Therapy Center; Department of Microbiology and Physiological Systems

Publication Date

2-28-2017

Document Type

Article

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Chemicals and Drugs | Endocrinology | Medical Physiology | Obstetrics and Gynecology | Oncology | Reproductive and Urinary Physiology | Therapeutics

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. 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.

Rights and Permissions

Freely available online through the PNAS open access option. Citation: Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1688-E1697. doi: 10.1073/pnas.1620729114. Epub 2017 Jan 30. Link to article on publisher's site

DOI of Published Version

10.1073/pnas.1620729114

Related Resources

Link to Article in PubMed

Keywords

AAV9, AMH, MIS, contraceptive, oncofertility

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

28137855

 
 

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