Characterization of residual ovarian tissue in mice following 4-vinylcyclohexene diepoxide-induced ovarian failure

Menopause is associated with disorders such as osteoporosis and ovarian cancer. It is unclear whether the postmenopausal ovary retains steroidogenic capacity and how it can impact the development of these disorders. The present studies used the VCD-treated follicle-depleted mouse model of menopause to test the hypothesis that residual ovarian tissue retains steroidogenic capacity following ovarian failure and, thus, affects the development of these disorders. Microarray technology was used to evaluate gene expression in residual ovarian tissue of follicle-depleted mice compared to that in ovaries from cycling animals. Among the genes identified were those encoding proteins for synthesis of androgens. Steroidogenic capacity of residual ovarian tissue was further evaluated by determining the expression of genes and proteins involved in ovarian steroidogenesis, and by measuring levels of circulating androstenedione and gonadotropins. Follicle-depleted ovaries were enriched in mRNAs for androgenic enzymes, receptors involved in the internalization of cholesterol, and luteinizing hormone receptor. Increased circulating levels of FSH and LH and detectable androstenedione were measured throughout the study. Protein for 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase/17,20-lyase and luteinizing hormone receptor was detected in follicle-depleted ovaries by Western blot analysis and localized by immunofluorescence staining. The contribution of retaining residual ovarian tissue to accelerated bone loss following ovarian failure was evaluated by comparing bone mineral density from young and aged VCD-treated mice to that in age-matched ovariectomized (OVX) animals. Retaining residual ovarian tissue resulted in protection against accelerated bone loss in young but not aged VCD-treated mice. Whether residual ovarian tissue is more susceptible to development of ovarian neoplasms compared to ovaries from cycling animals was addressed by combining the VCD-treated mouse with the DMBA model of ovarian carcinogenesis. VCD-treated follicle-depleted mice that received DMBA developed Sertoli-Leydig cell tumors while no tumors were observed in cycling animals. Residual ovarian tissue following ovarian failure appears to have a protective effect against loss of bone integrity, but a detrimental effect on development of ovarian neoplasms. Findings from these studies: provided evidence of a physiological role for residual ovarian tissue following ovarian failure, and furthered the use of the VCD-treated mouse as a relevant model for menopause and associated disorders.