Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women

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To compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology, and total cancer incidence among healthy postmenopausal women.

Study design: This study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17- beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo.

Main outcome measures: Participants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence.

Results: Over up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies, and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated.

Conclusion: Our results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women.

1. Introduction

Data strongly suggest that estrogen replacement therapy is associated with beneficial effects on cardiovascular disease (CVD) when initiated within 10 years of menopause [1,2]. Growing evidence for the timing hypothesis supports the effects of postmenopausal estrogen therapy on atherosclerosis and CVD depending on the timing of the initiation of hormone therapy (HT) relative to menopause, age, or both [3–5]. Estrogen hormone replacement most effectively slows atherosclerosis when underlying vascular tissue is healthy and maintains up-regulated estrogen receptors [5–8].

Despite the importance of timing of HT initiation, there is concern that combined estrogen-progestogen therapy may attenuate estrogen’s beneficial effects on cardiovascular health [9–11]. It is likely that the effects of progestins are mediated through progesterone receptors that are present in the arterial wall as well as affecting down-regulation of estrogen receptors. To minimize any possible negative progestogen effect on estrogen receptors in the arterial wall while testing for a beneficial effect of estradiol (E2) effects on atherosclerosis progression, the Early versus Late Intervention Trial with Estradiol (ELITE) protocol selected a low-dose vaginal micronized P4, 10 days each month in women with a uterus. The purpose of this post-hoc analysis is to evaluate the effect of oral E2 plus vaginal P4 on endometrial thickness, endometrial biopsy results, cervical cytology, and overall cancer incidence among healthy postmenopausal women during the ELITE follow-up.

The North American Menopause Society and the International Menopause Society require the use of a progestogen to oppose the E2 effect on the endometrium among postmenopausal women with an intact uterus [20–22]. Different routes, doses, and regimens of progestogen have varied effects on the endometrium, from no changes to the increased endometrial thickness and atrophic to endometrial hyperplasia and endometrial cancer [23,24]. Since vaginal P4 has a higher local endometrial effect than systemic P4 as determined by endometrial tissue P4 levels [25], vaginal P4 could potentially provide an alternative to systemic P4 with limited systemic effects [26]. However, given our data showing insufficient endometrial protection with the tested regimen, appropriate dose and regimen of vaginal P4 in conjunction with estrogen therapy requires further study to determine the optimal endometrial uterine protection. Our study emphasizes the importance of adequate exposure to progestogen to oppose the effect of estrogen on endometrial proliferation among postmenopausal women using hormone therapy.
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