Date of Award

Winter 1-2020

Degree Type

Thesis

Degree Name

Doctor of Philosophy In Regulatory Biology With Specialization In Cellular And Molecular Medicine

Department

Biological, Geological and Environmental Sciences

First Advisor

Tuohy, Vincent K.

Second Advisor

Dr. Anton Komar

Third Advisor

Dr. Xiaoxia Li

Abstract

Anti-Mullerian hormone (AMH) has been known since the mid-twentieth century as the substance secreted by the testes of the male fetus that is responsible for directing the proper development of the male reproductive organs from the primordial structures that would otherwise become the uterus and fallopian tubes. However, despite its longknown significance in male development, only recently has its importance in the adult female become evident. AMH is now considered to be not only a clinical indicator of the finite ovarian egg supply, but a vital regulator thereof throughout the reproductive life of the female. Dysfunctions in AMH regulation may lead to infertility that underlies conditions such as primary ovarian insufficiency (POI) and polycystic ovarian syndrome (PCOS). Moreover, mounting clinical and experimental evidence suggests that many such cases may be the result of autoimmunity to AMH. To test this hypothesis, an animal model of AMH autoimmunity was developed by immunization of C57BL/6J female mice with recombinant AMH protein. These mice developed a typical autoimmune profile with a robust antigen-specific type-1/type-17 immune response with high frequencies of CD4+ T cells that transiently infiltrated ovarian tissues as well as long-lasting high titers of IgG1 and IgG2b in the serum. Most importantly, the mice exhibited a unique and previously unreported phenotype in which their reproductive lifespan was extended. Mice immunized with AMH in complete Freund's adjuvant (CFA) remained fertile at ten months of age at a time when control mice immunized with CFA alone exhibited a viii natural decline in fertility due to reproductive senescence. AMH-immunized mice had more litters, greater numbers of pups per litter, and conserved more active follicles than controls at ten months. This effect correlated with a significant lengthening of the estrous cycle, resulting in fewer cycles over time which did not reduce the probability of conception or the health and viability of the offspring, but rather extended the fertile lifespan of the mice. This novel model of experimental autoimmune oophoritis (EAO) helps advance the knowledge of the physiologic role of AMH in the female, and may aid in understanding and managing human health conditions such as menopause and infertility.

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