Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50–59 Years of Age

Ross L. Prentice; Aaron K. Aragaki; Rowan T. Chlebowski; Jacques E. Rossouw; Garnet L. Anderson; Marcia L. Stefanick; Jean Wactawski-Wende; Lewis H. Kuller; Robert Wallace; Karen C. Johnson; Aladdin H. Shadyab; Margery Gass; JoAnn E. Manson


Am J Epidemiol. 2021;190(3):365-375. 

In This Article

Abstract and Introduction


The health benefits and risks of menopausal hormone therapy among women aged 50–59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50–79 years at 40 US clinical centers during 1993–1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993–2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50–59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.


Following the early stoppage in 2002[1] of the intervention in the Women's Health Initiative (WHI) trial of 0.625 mg/day conjugated equine estrogens (CEE) plus 2.5 mg/day medroxyprogesterone acetate (MPA), among 16,608 healthy postmenopausal women with a uterus, there was a substantial reduction in use of menopausal hormone therapy in the United States[2,3] and worldwide. The early intervention stoppage was motivated by an observed elevation in breast cancer risk, the trial's primary safety outcome, and by a lack of evidence of risk reduction for coronary heart disease (CHD), the primary efficacy outcome, or for cardiovascular diseases more generally. The 0.625 mg/day CEE trial, among 10,739 post-hysterectomy participants, was also stopped early in 2004,[4] based in part on a stroke elevation of similar magnitude to that seen in the CEE + MPA trial.

There was a strong interest at the WHI trial-design stage to include older postmenopausal women, to allow an examination of whether the hypothesized hormone therapy benefit for CHD would extend to older ages. Hence, women aged 50–79 years were eligible for enrollment, and special efforts to recruit older women led to 32.3%, 45.2%, and 22.5% of enrollees in the 50–59, 60–69, and 70–79 age groups, respectively. The question subsequently arose as to whether trial results differed from those hypothesized, at least in part, because trial enrollees were older and further from menopause onset compared with women in the community making hormone therapy decisions, frequently motivated by vasomotor symptom control. The topic is particularly germane for breast cancer where, over cumulative follow-up of 13 years, an anticipated significant increase was observed with CEE + MPA while an unexpected significant decrease was observed with CEE alone.[5] In contrast, a recent summary of worldwide observational data reported breast cancer risk increases with both estrogen-alone and estrogen + progestin regimens, with larger hazard ratios for the latter. In this report, the randomized trial evidence, mostly from the WHI trials, was described as "largely for hormone use starting after age 60 years".[6]

Here we report additional data, and additional data analyses, from the WHI hormone therapy trials, with a focus on participants who were 50–59 years of age, like many women considering hormone therapy in the community. Most trial participants continued postintervention follow-up beyond median intervention periods of 5.6 years in the CEE + MPA trial and 7.2 years in the CEE trial. Disease incidence[5] and mortality results,[7] including periodic National Death Index matching for all trial participants, have been reported through September 30, 2010, and December 31, 2014, respectively. Here we report results from follow-up through December 31, 2016.

Even with such substantial follow-up, the numbers of women experiencing some important clinical outcomes remains small when restricted to women of ages 50–59 years at enrollment, leading to an unclear balance of risks and benefits in this subset.[8] Consequently, to enhance precision, we present novel analyses using a "parsimonious" hazard ratio model that focuses on the age group 50–59 years while leveraging data from all randomized enrollees (see Methods). The clinical outcomes considered are the components of the protocol-defined global index, namely: CHD, (invasive) breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality. Additionally, we considered a multivariate global index that utilizes all the multiple global index outcomes, rather than just a participant's earliest postrandomization outcome, in an effort to enhance precision of global benefit versus risk assessments.[9,10]