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Summer 2008 Declining Ovarian Reserve…A Critical Determinant of Reproductive HealthThe US healthcare system expends billions of dollars annually in the management of osteoporotic fractures and cardiovascular disease (CVD) in women, major morbidities associated with the postmenopausal period (Figure 1) (1, 2).
A growing body of evidence suggests that a replete estrogenic milieu confers protection against initiation of processes that underlie these two disease entities. Deteriorating skeletal and cardiovascular profiles correlate with cessation of ovarian function, i.e. menopause. While the skeletal benefits of estrogen are well recognized across all ages in women, cardio–protective implications are thus far substantiated only for endogenous estrogens. Accruing data add credence to the hypothesis that, if commenced prior to initiation of atherosclerosis, exogenous estrogen therapy is also likely to confer cardio–protection in menopausal women. Researchers are hard at work to validate the theory that the timing of menopausal estrogen therapy may be a decisive determinant in conferring such cardio–protection. (3) The past few decades have witnessed substantial advances in secondary prevention of varied diseases; however, there have been far fewer similar successes in primary prevention. A sparse, yet accruing body of literature provides tangible evidence of initiation of processes that underlie both CVD and skeletal attrition concomitant with premenopausal decline in ovarian physiology (4); appreciation of this physiological phenomenon may indeed hold the answer to success with primary prevention strategies. The term “ovarian reserve” is a quantitative estimate of ovarian function, a concept that has emerged and been validated in the era of assisted reproduction. (5) Declining ovarian reserve prior to menopause reflects the relatively early loss of ovarian hormone production and identifies reproductive aging as a continuum. The hormonal profile of decreased ovarian reserve in young women shares features with the profiles of older perimenopausal women, i.e., a hypo–estrogenic (6) (Figure 2) and hypoandrogenic (7) (Figure 3) milieu in premenopausal women with diminished ovarian reserve identifies mechanisms that may be of pathogenic significance in the initiation of processes that specifically underlie skeletal loss and CVD.
Indeed, a significant correlation between increasing serum levels of follicle stimulating hormone (FSH), a recognized marker of declining ovarian reserve, with an up–regulated state of bone turnover (as reflected by composite score of serum bone formation and resorption markers) was noted in health albeit infertile premenopausal women (Figure 4). (8)
Of note, on adjusted analyses, diminished ovarian reserve emerged as an independent predictor of enhanced bone turnover and of low bone mineral density, after adjusting for parameters known to influence skeletal metabolism (age, BMI, race, smoking and menstrual regularity) (8), providing supportive evidence of initiation of skeletal attrition concomitant with declining ovarian reserve in the premenopausal years. Interestingly, a similar association is emerging between a deteriorating CVD risk profile and decline in ovarian reserve in premenopausal women (9); analyses of age–restricted data for healthy women between ages 35 and 45 enrolled in NHANES (representing the healthy population of the USA) for years 1999–2002 demonstrated worsening biomarkers recognized as surrogates for CVD (homocysteine, insulin and ferritin levels); of interest, these associations were most robust in those of a normal BMI (‹25Kg/M2). Of even greater interest was the observed increase in blood pressure (systolic and diastolic) in association with declining ovarian reserve (as reflected by increasing FSH levels) in this cross–sectional population of healthy premenopausal women; after adjusting for age, BMI, race, physical activity, socio–economic status, menstrual regularity and smoking status, premenopausal women with serum FSH between 10 and 19.99mIU/ml demonstrated significantly higher diastolic BP (2.84mm Hg, 95% CI 0.28–5.40mm Hg) compared to those with FSH level ‹10mIU/ml (p=0.031). Taken together, these data suggest that cardio–deleterious and osseo–deleterious processes are initiated concomitant with declining ovarian reserve in premenopausal years (Figure 5). (10)
The success of “primary prevention” lies in successfully aborting the cascade of pathogenic phenomena that underlie pathophysiological processes prior to the establishment of disease. Timely intervention is thus critical to the success of any preventive approach. Given the overwhelming morbidity contributed by skeletal fragility and CVD in an aging female population, and the existing “snapshots” identifying initiation of contributory pathophysiological processes in the premenopausal years, it is imperative to appreciate the importance of targeting preventive strategies concomitant with a decline in ovarian physiology in the years predating the final menstrual period; while the track record of the medical community regarding “primary prevention” has been far from stellar, the suggested approach is likely to be successful in translating into a reduced magnitude of community health care burden attributable to fragility fractures and CVD. References:
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