Modulation of ovarian structure and abdominal obesity in curcumin- and flutamide-treated aging FSH-R haploinsufficient mice.

We have previously shown that follicle-stimulating hormone receptor haploinsufficient mice undergo early reproductive senescence with alterations in ovarian structures. The objective of this study was to treat aging (7-8 months) +/- follicle-stimulating hormone receptor mice that are destined for reproductive failure with 2 selected antiandrogens, curcumin and flutamide, to counteract deleterious effects of mild hyperandrogenemia on the ovary and metabolism. Both compounds significantly downregulated the expression of ovarian androgen receptor protein and simultaneously reduced cyclooxygenase 2 protein in the ovary. Immunolocalization of bone morphogenetic protein-15 in the ovary was enhanced considerably by curcumin and partially by flutamide in treated mice. Improved structural changes were evident in zona pellucida of curcumin-treated ovaries. Flutamide reduced p450c-17 (cyp-17 protein) enzyme expression in thecal/interstitial cells, whereas increased expression of 3beta-hydroxysteroid dehydrogenase in thecal cells and granulosa-lutein cells of big follicles was apparent in curcumin-treated ovaries. Reduction in abdominal adiposity was greater in flutamide-treated mice. Taken together, our study allows the following conclusions: changes in ovarian histology and oocyte components as well as adipose tissue indicate the potential for reversing ovarian decline and metabolism because of mild hyperandrogenemia that occurs with aging in follicle-stimulating hormone receptor haploinsufficienct mice.

Recent female mouse models displaying advanced reproductive aging.

Reproductive senescence occurs in all female mammals with resultant changes in numerous body functional systems and several important features may be species-specific. Those features that appear to parallel human menopause and aging include general similarity of hormone profiles across the menopausal transition, progression to cycle termination through irregular cycles, declining fertility with age, disturbances in thermogenesis, age-related gains in body weight, fat distribution and disposition towards metabolic syndrome. Structural and hormonal changes in the brain and ovary play a critical role in determining the onset of reproductive senescence. The short life span of rodents such as mice (compared to humans) and the ability to generate specific and timed gene deletions, provide powerful experimental paradigms to understand the molecular and functional changes that precede and follow the loss of reproductive capacity. In theory, any manipulation that compromises ovarian function either partly or totally would impact reproductive events at various levels followed by other dysfunctions. In this article, we provide an overview of three mouse models for the study of female reproductive aging. They are derived from different strategies and their age related phenotypes have been characterized to varying degrees. The follitropin receptor knockout (FORKO) mouse, in its null and haploinsufficient state as well as the dioxin/aryl hydrocarbon receptor (AhR) knockout mouse, serve as two examples of single gene deletions. A third model, using administration of a chemical toxicant such as 4-vinylcyclohexene diepoxide (VCD) in the adult state, produces ovarian deficiencies accompanied by aging changes. These will serve as useful alternatives to previously used radical ovariectomy in young adults. It is anticipated that these new models and more that will be forthcoming will extend opportunities to understand reproductive aging and resolve controversies that abound on issues related to benefits and risks of hormone replacement therapy or other modalities for improving quality of life.