Health & Medical Menopause health

Product Labeling for Low-dose Vaginal Estrogen

Product Labeling for Low-dose Vaginal Estrogen

Low-Dose Vaginal Estrogen and the Endometrium

Endometrial tissue response is an extremely sensitive bioassay for estrogenic action and reflects the integration of serum estrogen levels with duration of estrogenic exposure. Three different low-dose vaginal estrogen therapies have been evaluated, and their endometrial effects have been assessed via either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. The largest trial to date is a randomized double-blind controlled study of 1,612 postmenopausal women in which vaginal estradiol tablets were administered at a dose of 25 µg/day for 2 weeks, followed by a dose of 25 µg two times a week for 12 months. This study demonstrated no increases in serum estradiol levels at 4 and 12 months compared with baseline levels: (mean [SD], 15.7 [2.3] pg/mL {baseline} vs 15.5 [2.5] pg/mL {12 mo}). Vaginal ultrasound–determined endometrial thickness remained essentially unchanged after 12 months of therapy (mean [SD], 3.1 [0.4] mm {baseline} vs 2.9 [0.5] mm {12 mo}). There was no change in uterine volume or enlargement of preexisting myomas across 12 months. In a separate study of a vaginal estradiol tablet 10 µg/day, endometrial biopsies were performed in 297 women after 12 months of treatment; 183 women had endometrial tissue that was atrophic or inactive, whereas 111 women had no tissue or had insufficient tissue for diagnosis. There was one case of complex hyperplasia without atypia. Similar findings have been reported in a trial of estradiol vaginal cream given at a dose of 10µg/day for 3 weeks then 10 µg two times a week. Endometrial thickness remained stable at less than 5 mm during the 12-week treatment. Moreover, in a randomized study of a low-dose vaginal estradiol ring delivering estradiol 7.5 µg/day, estradiol levels increased less than 1 pg/mL above baseline (P=0.59)and endometrial lining thickness at 12 months was similar to baseline, with a mean (SD) change of −0.14 (0.53) mm (P=0.54).

If low-dose vaginal estrogens have either regional or systemic effects beyond their local action, one would expect to observe endometrial proliferation, as determined by either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. Collectively, these studies demonstrate that low-dose vaginal estrogen therapy, including assessments of three different estradiol preparations at 12 months of evaluation, does not seem to have significant endometrial impact beyond the local vaginal estrogenic effects. Higher dosing, long-term use, and use by women with comorbidities may carry higher risks.

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