Women's Health Initiative

After 18 years of follow-up, women who used combination therapy for approximately 5 years or estrogen alone for approximately 7 years did not have increased all-cause, cardiovascular, or cancer mortality. Most WHI participants were 10 or more years past menopause, making the results poorly applicable to perimenopause or early postmenopause. The WHI studied only oral CEE and oral MPA, so results cannot be extrapolated to other estrogen types, progestogens, or non-oral delivery routes. A 2018 reanalysis found no effect on breast cancer incidence from CEE + MPA after excluding prior estrogen users from the placebo group. The timing hypothesis holds that initiating hormones earlier after menopause onset provides greater cardiovascular benefit and potentially less harm than late initiation, though it remains an active area of debate. Twenty-year WHI follow-up data found that ovarian cancer incidence and mortality more than doubled among women on estrogen alone, with the difference reaching statistical significance after 12 years.