Clinical trials failed to show a beneficial effect of
postmenopausal hormone replacement therapy, whereas experimental studies in young animals reported a protective function of
estrogen replacement in
cardiovascular disease. Because these diverging results could in part be explained by aging effects, we compared the efficacy of
estrogen substitution to modulate
cardiac hypertrophy and cardiac gene expression among young (age 3 months) and senescent (age 24 months) spontaneously hypertensive rats (SHRs), which were
sham operated or ovariectomized and injected with placebo or identical doses of 17beta-estradiol (E2; 2 microg/kg
body weight per day) for 6 weeks (n=10/group). Blood pressure was comparable among
sham-operated senescent and young SHRs and not altered by
ovariectomy or E2 treatment among young or among senescent rats.
Estrogen substitution inhibited uterus
atrophy and gain of
body weight in young and senescent ovariectomized SHRs, but
cardiac hypertrophy was attenuated only in young rats. Cardiac
estrogen receptor-alpha expression was lower in intact and in ovariectomized senescent compared with young SHRs and increased with
estradiol substitution in aged rats. Plasma
estradiol and
estrone levels were lower not only in
sham-operated but surprisingly also in E2-substituted senescent SHRs and associated with a reduction of hepatic
17beta-hydroxysteroid dehydrogenase type 1
enzyme activity, which converts weak (ie,
estrone) into potent
estrogens, such as E2. Aging attenuates the antihypertrophic effect of
estradiol in female SHRs and is associated with profound alterations in cardiac
estrogen receptor-alpha expression and
estradiol metabolism. These observations contribute to explain the lower efficiency of
estrogen substitution in senescent SHRs.