UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS), a disorder characterized by abnormal menstrual cycles and evidence of increased male hormone production, is the most common endocrinopathy affecting women. It is estimated that 5-10% of reproductive age women may have some variant of this disease process. Increasingly, an association between insulin resistance and PCOS has been described. It remains unclear whether insulin is associated with the mechanism of anovulation in PCOS. This insulin resistance does appear, however, to increase the risk for development of diabetes and cardiovascular disease. This increased risk, and its significant impact on long-term morbidity and mortality, make the understanding of this disease process critically important to public health.

We envision the development of a combined clinical and basic science program for the study of PCOS. As part of this multiprong approach, we will continue studies currently underway with a cohort of young women followed from age 9 to 19. Current investigations will ascertain whether insulin resistance is critical to disease development. In studying this cohort, our aim is to facilitate a better understanding of the factors responsible for the development and progression of the disease, as well as, allowing for subsequent prospective studies with the intent of preventing disease development. Further, we have established a multi-disciplinary group of investigators to develop a comprehensive PCOS Clinic. This facility will establish data and tissue banks and serve as a resource for future clinical investigation.

PCOS patients are almost always infertile as their failure to ovulate prevents a scheduled pregnancy. The mechanism(s) responsible for the arrest of egg development in PCOS is not well understood. Studies suggest the presence of a local factor that may inhibit follicle stimulating hormone (FSH). Most of the prior studies utilized ovaries obtained at the time of gynecologic surgery. Thus once removed, they were not available for further manipulation and re-evaluation. Our approach is to directly sample the follicular environment in the intact subject, with the opportunity to apply pharmacologic intervention (agents which lower insulin levels +/- agents which decrease androgen production) followed by re-sampling. This will enable us to directly assess the effect(s) of changes in circulating insulin levels and/or changes in intra-ovarian androgen production, on egg development within the patient.

Perimenopause: Improving Our Understanding of Aging

As the female population ages and spends more than one-third of their lives post-menopausal, understanding those factors which impact on the rate of aging and its implications for later health become increasingly important. Working in collaboration with Dr. Renee Reijo, from the CRS, and Dr. Barbara Sternfeld, epidemiologist at Kaiser Department of Research, we propose a population-based study of reproductive aging. This study will develop new clinical markers of ovarian aging and correlate these markers with specific genes and interacting proteins that appear to be important in oocyte development and survival. A longitudinal component of this study will follow the cohort prospectively to better understand reproductive aging and the impact of environmental factors.

Women who continue to maintain regular menses, as they enter the fifth decade, begin to report increasing physical and psychological changes. Preceding the onset of these changes is a decline in growth hormone (GH) levels and activity (somatopause). Many alterations in function and structure, such as changes in muscle mass, adipose tissue and bone density, which occur with aging, may be linked to this relative deficiency of GH. We hypothesize that changes in the GH axis also lead to abnormalities in hypothalamic-pituitary function and a subsequent decline in ovulatory and psychological functioning. Our secondary hypothesis is that re-establishment of normal GH activity will correct abnormal hypothalamic-pituitary function leading to partial, or complete normalization of ovarian function and improvement in psychological symptomatology. One would not expect alterations in GH to restore complete ovarian function once the oocyte pool has been depleted. However, a better understanding of the acceleration of oocyte depletion seen in the late 30's might improve fertility outcome and adverse effects of aging in women in a more natural way. The goal of therapy in this group of women is to enhance longevity and quality of life. This requires a complete understanding of the changing endocrine milieu, those changes which increase risk for symptomatology, and the effects of available treatment options.

Selected References

Cedars MI: Polycystic Ovary Syndrome: What Is It and How Should We Treat It? J Pediatr 2004 144:4-6.

Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N: KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric 2005 8:3-12.

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