In October 2012, the U.S. Preventive Services Task Force (USPSTF) released a final statement recommending against the use of combined estrogen and progestin (E+P) to prevent chronic conditions in women who have experienced menopause. The USPSTF also recommended against use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.
The USPSTF is an independent group of experts, which makes recommendations regarding the efficacy of particular clinical interventions. Recommendations are based on an assessment of evidence as to the relative benefits and harms of a specific clinical treatment, without regard to costs of therapy. The USPSTF notes that treatment should be individualized to the patient or situation.
The recommendations against use of E+P or of E alone in preventing chronic conditions are grade D recommendations, meaning "there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits," according to the USPSTF. Key findings from the recommendation statement are shown in the Table.
The recommendation does not pertain to the use of hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness, as the USPTSF states that this topic falls outside of its scope. The recommendation also does not apply to women younger than 50 years of age who have undergone surgical menopause.
This recommendation is in alignment with recommendations from many major health organizations, including the American Heart Association, American Congress of Obstetricians and Gynecologists, and the American Academy of Family Physicians. The USPSTF issued a similar recommendation in 2005. The recent update was based upon a comprehensive review of the literature published since that time.
Benefits: Hormone replacement therapy (HRT) (combined E+Pa or unopposed E) is associated with a decreased risk for fractures in postmenopausal women.
The benefits of hormone therapy for prevention of chronic disease are unlikely to outweigh the harms in postmenopausal women (whether combined treatment or, in women post-hysterectomy, unopposed E.)
Neither combined estrogen and progestin therapy nor estrogen alone reduces the risk for coronary heart disease in postmenopausal women and probably increases the risk for its occurrence.
aOral conjugated equine estrogen 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day USPSTF, U.S. Preventive Services Task Force.
Moyer VA. U.S. Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(1):47-54.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in reproductive and neuroendocrinology, and an Attending in Medicine, Massachusetts General Hospital, Boston, MA.
The USPSTF undertook an update to their 2005 recommendations regarding the effectiveness of hormone therapy for the prevention of chronic conditions—eg, cardiovascular disease and osteoporosis—as well as an exploration of whether the risk-benefit profile was different in certain subpopulations. Only randomized placebo-controlled clinical trials were included in the literature review for this update. The authors remark that of the 9 trials they evaluated, only the Women's Health Initiative (WHI) was powered to evaluate HRT versus placebo for primary prevention of multiple chronic conditions, and they thus draw any quantitative comparisons from those results.
The guideline's population of interest is postmenopausal women ≥50 years, and does not include women with premature menopause or menopause due to surgery. The treatments of interest are combined therapy—ie, estrogen and progestin—and, in women post-hysterectomy, unopposed estrogen. [Unopposed estrogen is linked to an increased risk of uterine cancer, and thus is not used in women with a uterus.] It is useful to note that the baseline characteristics of the women who received E+P and those who received unopposed E are not the same, so while data are presented for both, they should not be compared to one another. The analysis of risks and benefits analysis is targeted only to the prevention of chronic conditions, and not toward the relief of symptoms.
The bulk of the evidence supported an association with reduced fracture risk with both combined treatment and unopposed estrogen. However, the USPSTF felt this benefit was outweighed by the association with an increased risk of stroke, dementia (combined therapy alone), incontinence (after 1 year of use, in women without a history of incontinence), and gallbladder disease, as well as what is categorized as a small increase in deep venous thrombosis/pulmonary embolism. The association with dementia was drawn from the WHI memory study involving women aged 65 to 79 years, in which the 4 year follow-up showed an increased risk of probable dementia in women receiving E+P (HR 2.05, CI 1.21-3.48), but no statistically significant difference with unopposed E. When mild cognitive impairment alone was examined, there was no statistically significant increase.
Areas of particular interest include fractures (for which both E+P and unopposed E showed a benefit), coronary heart disease (CHD), and breast cancer. The USPSTF concluded that E+P does not decrease the risk of CHD but in fact, might increase it (hazard ratio 1.22 in WHI results for women 50-79 years of age, but with 95% CI 0.99-1.50). Breast cancer was another area of interest. Estrogen plus progestin appeared to be associated with a small increase in both invasive breast cancer and death due to breast cancer. In contrast, the risk of both appeared slightly decreased with unopposed E; this effect, the guidelines suggest, may have come from a subpopulation without family or personal history.
There has been increasing attention paid to the timing and duration of treatment. The USPSTF noted that there have not been randomized controlled trials (RCTs) to evaluate the impact of HRT timing relative to menopause. The guideline concludes that, while some analyses suggest that risk increases with age of initiation and duration of use, the findings are not consistent and do not tend to reach statistical significance. However, it does include findings from a WHI subgroup analysis showing that coronary heart disease may be reduced in the youngest age group studied (50 to 59 years; HR 0.59, CI 0.38-0.90).
The guidelines also cite the recommendations of other medical associations, such as the recommendation against use of HRT for primary or secondary prevention of cardiovascular disease (CVD) by American Heart Association and American Congress of Obstetricians and Gynecologists, the recommendation against use for prevention of cognitive aging or coronary protection by North American Menopause Society (which also notes the importance of individual factors, including quality of life), and the recommendation against using HRT for prevention of chronic conditions generally by the Canadian Task Force on Preventive Health Care and American Academy of Family Physicians.
USPSTF based its guidelines on the particular studies reviewed, with hazard ratios drawn specifically from the WHI; as is noted later in this Endoscan, studies of younger cohorts with earlier treatment or different HRT formulations may suggest different conclusions. In the subsequent reviews in this issue of EndoScan, we further examine the effect of HRT timing, and discuss in greater detail recent studies and reviews on the effect of HRT on cardiovascular health, breast cancer, and cognition in greater detail.