Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels.

CONTEXT

The use of systemic estrogens for the treatment of menopausal symptoms has declined by approximately 80% following the initial publication of the Women's Health Initiative in 2002. Current attention focuses on vaginal estrogen as a local therapeutic means to achieve control of symptoms due to vulvovaginal atrophy without increasing plasma estradiol levels. A key issue is whether or not vaginally administered estrogens are absorbed and produce systemic effects.

EVIDENCE ACQUISITION

Medline and PubMed were searched for relevant English-language articles using pertinent key words. The bibliographies of the pertinent articles were then read to identify further relevant articles.

EVIDENCE SYNTHESIS

Several confounding factors influenced the data analysis including: (1) estradiol assay sensitivity and specificity; (2) acute versus chronic absorption; (3) delivery systems, doses, timing, and formulation; and (4) effect of atrophic versus mature vaginal mucosa on absorption. Each preparation was associated with acute estradiol absorption with peaks at approximately 8 h and return to baseline at 12 h. Low-dose vaginal estrogen, arbitrarily defined as the 7.5-μg vaginal ring and 10-μg tablet, increased plasma estradiol levels during chronic administration but not above the normal range of ≤ 20 pg/ml. Surprisingly, these increments were associated with systemic effects to lower plasma levels of low density lipoprotein cholesterol and bone resorption rates. Intermediate doses (i.e. 25 μg estradiol or 0.3 mg conjugated equine estrogen) resulted in plasma estradiol levels approaching or exceeding 20 pg/ml. The higher doses (50-2000 μg estradiol or 0.625-2.5 mg conjugated equine estrogen) resulted in premenopausal levels of estrogen.

CONCLUSIONS

Low-dose vaginal estrogen appears to be an effective strategy for managing women whose symptoms result from vulvovaginal atrophy. These regimens limit but do not completely eliminate systemic absorption. Low-doses regimens should be preferred clinically to intermediate- or high-dose methods.