Estradiol Patches

The twice-weekly estradiol transdermal system was studied in two controlled clinical trials in a total of 356 women, in which the 0.075 mg and 0.1 mg per day doses were superior to placebo in relieving vasomotor symptoms at week 4 and maintained that through weeks 8 and 12. Because the 0.0375 mg and 0.05 mg doses did not separate from placebo until roughly week 6 in those trials, a third 12-week placebo-controlled trial was run in 255 women whose baseline mean was 11.5 hot flushes a day; the lowest 0.0375 mg dose was superior to placebo on both frequency and severity at weeks 4, 8 and 12.¹

In a separate randomized trial of 214 women aged 25 to 74 assigned to a 0.05 mg per day estradiol patch, a 0.1 mg per day patch or placebo, with adequate efficacy data from 191, the mean weekly hot flush rate across all treatment cycles fell from 46 to 20 on the 0.05 mg patch, a 67 percent reduction, and from 52 to 16 on the 0.1 mg patch, a 72 percent reduction, against a fall from 53 to 46 on placebo, an 18.1 percent reduction. Both estradiol groups were statistically significantly better than placebo, p less than 0.05.²

Bone was measured in its own trial. In a 2-year double-blind, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally menopausal women within five years of menopause and without osteoporosis, mean age 52, were assigned to one of four doses of the twice-weekly estradiol transdermal system, 194 women, or placebo, 67 women, with non-hysterectomized women also taking oral medroxyprogesterone acetate 2.5 mg a day. Lumbar spine bone mineral density rose in every estradiol dose group and fell in the placebo group, and every estradiol dose was significantly superior to placebo, p less than 0.05, at all time points except the 0.05 mg dose at 6 months.¹

The Women’s Health Initiative ran two separate randomized, double-blind, placebo-controlled trials, and they did not find the same thing. In 16,608 postmenopausal women aged 50 to 79 with a uterus given oral conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg, hazard ratios over a mean 5.2 years were 1.29 for coronary heart disease, 95 percent confidence interval 1.02 to 1.63, 1.26 for invasive breast cancer, 1.00 to 1.59, 1.41 for stroke, 1.07 to 1.85, and 2.13 for pulmonary embolism, 1.39 to 3.25.³ In 10,739 women with a prior hysterectomy given conjugated equine estrogens alone for an average 6.8 years, stroke rose, hazard ratio 1.39, 1.10 to 1.77, hip fracture fell, 0.61, 0.41 to 0.91, coronary heart disease was unchanged, 0.91, 0.75 to 1.12, and breast cancer was 0.77, 0.59 to 1.01.⁴ A prespecified analysis of both trials found the coronary result varied with time since menopause, hazard ratio 0.76 at under 10 years, 1.10 at 10 to 19 years and 1.28 at 20 or more years, p for trend 0.02, while stroke risk was elevated regardless of timing, 1.32, 1.12 to 1.56.⁵

Route has been studied observationally rather than randomly. In two nested case-control studies covering 80,396 women aged 40 to 79 with a first venous thromboembolism between 1998 and 2017 and 391,494 matched controls drawn from UK general practice records, oral hormone therapy was associated with an adjusted odds ratio of 1.58 for venous thromboembolism, 95 percent confidence interval 1.52 to 1.64, while transdermal preparations were not associated with increased risk, adjusted odds ratio 0.93, 0.87 to 1.01.⁶