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

Motohiro Kano, Amanda E. Sosulski, Li Hua Zhang, Hatice D. Saatcioglu, Dan Wang, Nicholas Nagykery, Mary E. Sabatini, Guangping Gao, Patricia K. Donahoe, David Pépin

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 withmale 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 andwere 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.

Original languageEnglish
Pages (from-to)E1688-E1697
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number9
DOIs
Publication statusPublished - 2017 Feb 28
Externally publishedYes

Fingerprint

Contraceptive Agents
Dependovirus
Drug Therapy
Primary Ovarian Insufficiency
Ovary
Contraception
Hypogonadism
Granulosa Cells
Carboplatin
Menopause
Recombinant Proteins
Genetic Therapy
Doxorubicin
Cyclophosphamide
Ovarian Reserve
Proteins
Hormones
Serogroup
Therapeutics

Keywords

  • AAV9
  • AMH
  • Contraceptive
  • MIS
  • Oncofertility

ASJC Scopus subject areas

  • General

Cite this

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. / Kano, Motohiro; Sosulski, Amanda E.; Zhang, Li Hua; Saatcioglu, Hatice D.; Wang, Dan; Nagykery, Nicholas; Sabatini, Mary E.; Gao, Guangping; Donahoe, Patricia K.; Pépin, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 9, 28.02.2017, p. E1688-E1697.

Research output: Contribution to journalArticle

Kano, M, Sosulski, AE, Zhang, LH, Saatcioglu, HD, Wang, D, Nagykery, N, Sabatini, ME, Gao, G, Donahoe, PK & Pépin, D 2017, 'AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 9, pp. E1688-E1697. https://doi.org/10.1073/pnas.1620729114
Kano, Motohiro ; Sosulski, Amanda E. ; Zhang, Li Hua ; Saatcioglu, Hatice D. ; Wang, Dan ; Nagykery, Nicholas ; Sabatini, Mary E. ; Gao, Guangping ; Donahoe, Patricia K. ; Pépin, David. / AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 9. pp. E1688-E1697.
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