A recent study—Dose-Response Effect of Estrogen on the Kidney and Heart—reveals that estrogen replacement therapy (ERT) may increase the risk of cardiovascular disease. A study in mice examined whether adverse effects of ERT are related to doses used and found moderate and high doses of ERT increased problems in the kidney and heart, suggesting ERT dosage may be an important factor in a woman’s overall health. The study was conducted by Xiaomei Meng, Martin Antonio D’Ambrosio, Tang-Dong Liao, and Xiao-Ping Yang, members of the Hypertension and Vascular Research Division of Henry Ford Hospital, Detroit, Michigan.
The frequency of cardiovascular disease (CVD) and related deaths were significantly lower in premenopausal women than in men of similar age. Meanwhile, the female gender advantage decreases or disappears with increased age and reduced estrogen levels following menopause, which suggests ovarian hormones, probably estrogen, protect women against CVD. Also, studies confirm postmenopausal women who receive hormonal replacement therapy (HRT) have a lower incidence of CVD and die less frequently than those not on HRT. Because of this, HRT is routinely used for prevention of CVD in postmenopausal women. Unfortunately, recently published data by the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI) confirmed an unfavorable effect of HRT on the risk and events of CVD in women.
While data were convincing, there are other considerations such as composition of the drugs, dosage, time when HRT was initiated, age, and pre-existing risk factors for CVD, which may have affected the outcome of the HERS and WHI studies. For instance, estrogen dosage may also be a contributing factor in the unfavorable outcome of HRT since it has been shown that certain types of estrogen can decrease heart attacks and stroke in women who have no history of CVD. On the other hand, certain estrogen levels, when combined with progestin, increase the risk of stroke.
To isolate these conflicting factors in the estrogen-CVD connection and understand the role of drug dosing, researchers examined if adverse effects of ERT were linked to the doses in mice. The researchers found that moderate and high ERT doses increased plasma estrogen levels four-fold and were associated with fluid retention in the uterus, amounts of protein in the urine, and dilated kidneys. Conversely, low E2 doses restored plasma estrogen to levels similar to the control groups; neither fluid retention nor renal damage was found in this group. Moderate and high E2 doses increased atrial natriuretic peptide (ANP), a cardiac hormone that when increased is an indicator of heart failure severity. At low level dosing this did not occur. Also, overall blood pressure and cardiac function were not changed by ERT at any dose.
“This shows that the size of the estrogen dose may be critical in determining whether ERT leads to cardiovascular or kidney disease,” said Dr. Yang, the study’s lead researcher. Other factors such as estrogen-to-progestin ratios, age of ERT onset, and the patient’s cardiovascular health when treatment is initiated may also be important factors, added Yang.
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