Menopause Live from IMS

Fung and colleagues have recently reported on a cross-sectional study, followed by a prospective analysis, on the effect of continuous postmenopausal estrogen therapy over a period of 10 years on blood pressure, microalbuminuria and renal function [1]. A total of 1044 postmenopausal women (mean age 72 years) were evaluated cross-sectionally between 1992 and 1996. These women formed the baseline of the study and 443 women from this population were re-evaluated 10 years later (2002–2005). The associations of estrogen therapy with blood pressure, urine albumin/creatinine ratio, glomerular filtration rate, chronic kidney disease and albuminuria were determined in this study. In the cross-sectional analyses, current users (for an average duration of 16.5 years) had lower diastolic blood pressure and lower odds of having hypertension and chronic kidney disease, independent of covariates. Current users also had the lowest body mass index and serum creatinine levels when compared to past or never-users. Both diabetes and chronic kidney disease were more common in never-users. A total of 443 participants (60% of survivors) returned for the follow-up visit some 10 years later (87 never-users, 247 past users and 109 current users). After age adjustment, statistically significant differences between the three groups were found only for the albumin/creatinine ratio. Differences in body mass index, systolic or diastolic blood pressure, and glomerular filtration rate did not reach statistical significance although estrogen therapy seemed beneficial. Mean diastolic blood pressure declined over time in current users, whereas systolic blood pressure increased among never-users.

Comment
Microalbuminuria is a marker of endothelial dysfunction and often precedes hypertension and chronic kidney disease. It may also serve as a marker of disease severity [2] and is associated with a higher risk of cardiovascular disease and mortality [3]. Several studies, both in humans and animals [4,5], have shown that estrogen has a vasodilatory effect on vascular smooth muscle, mediated through an increased release and decreased breakdown of nitric oxide. These result in an anti-inflammatory reaction and decreased vascular oxidative stress, which lead to vasoprotection and improvement in blood pressure and glomerular filtration rate. However, the long-term effects of estrogen therapy on kidney functions have been poorly studied so far and the results obtained have been mixed and hence not well defined [6-12]. The study of Fung and colleagues [1] fills this gap, being able to follow hormone users for the long term despite the results of the Women’s Health Initiative and the decline in estrogen therapy use which occurred while the study was ongoing. Participants took Premarin at 0.625 mg daily, thus avoiding inconsistent results obtained in previous studies using a variety of hormonal products, doses and routes of administration [13-15]. Other potential advantages of this study were the strict adherence to a well characterized protocol and the fact that biochemistry was performed by a single laboratory. However, the inconsistent effects of estrogen therapy on kidney functions (significant reduction in urinary albumin/creatinine ratio but insignificant effect on glomerular filtration rate and blood pressure) make it difficult to assess the actual overall impact of long-term estrogen therapy on chronic kidney disease. Also, the fact that postmenopausal hormone therapy is now recommended for young, symptomatic women is in contrast to this cohort which consisted of elderly, asymptomatic women. It is noteworthy that a large fraction of the participants had an intact uterus, but endometrial safety issues concerning the fact that they received long-term estrogen-alone (without progestogen) were not reported. This may be explained by the well-accepted practice back in the early 1990s, when the study was initiated, to prescribe unopposed estrogen even to non-hysterectomized women. 

To conclude, the study suggested that long-term use of estrogen therapy is associated with a reduction in microalbuminuria, a marker of microvascular disease; however, whether or not microvascular disease is affected by long-term estrogen therapy remains an open question. Evaluation of the effects of estrogen–progestogen treatment on microvascular disease is also warranted.

Duru Shah
Chairman, Indian College of Obstetricians & Gynecologists, Mumbai, India

References
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http://www.ncbi.nlm.nih.gov/pubmed/21326121
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