Aging women show a reduction in the number of germ cells and the number of ovulations, ovarian atrophy, cessation of cycling, and an increase in the incidence of ovarian tumors. Since ovarian tumorigenesis is associated with changes in both endocrinological and immunological function, we plan an in-depth analysis of these changes in an experimentally induced animal model. We will use a mouse strain in which complete removal of the neonatal thymus between 2 to 4 days of age results in ovarian dysgenesis characterized by the early loss of oocytes and follicles, then an increased incidence of ovarian tumors. Substantial preliminary data indicate that the experimental autoimmune oophoritis is associated with changes in both immunological and endocrinological function. The thymectomized females produce circulating autoantibodies against the ooplasma of the oocytes and have altered levels of circulating hormones. The purpose of the research is to study the nature of the thymus-ovarian axis and the implications of the interrelationship for a better understanding of ovarian tumorigenesis.
The specific aims will be carried out by comparing intact, sham thymectomized, and thymectomized females. We will: (1) characterize the vaginal cycles--length, regularity, and cytohormonal asseasments; (2) characterize the serum--total protein evaluation; RID analyses of the immunoglobulins, C3 complement, C-reactive protein, and alpha-1-fetoprotein; RIA circulating hormones--LH, FSH, estradiol, testosterone, progesterone, corticosterone, and thymosin-alphal; (3) characterize the circulating leukocytes--WBC counts and differential analysis; B- and T-cell ratios; T-cell subset analysis; and (4) attempt to prevent or retard ovarian tumorigenesis by treatment with thymosin fraction 5, antisera to thymosin-alphal, or antisera to the gonadotropins. Successful conclusion of this project will provide a comprehensive endocrinological and immunological analysis of ovarian tumorigenesis that will contribute to a database that should provide valuable insights into the pathogenic mechanisms of ovarian cancer. Further, this research may suggest therapeutic rationales for the early detection, prevention, or treatment of human ovarian cancer. (HF)
