Should estrogen therapy be given to postmenopausal women?
This has been an area of controversy since the completion of the Women’s Health Initiative (WHI) trials almost 15 years ago. Similar to debates about testosterone supplementation, there is ongoing controversy regarding criteria for who should be treated (e.g., age, years menopausal, symptomatic), by what formulation (e.g., conjugated estrogens versus estradiol, progesterone versus medroxyprogesterone acetate [MPA], continuous versus intermittent progestins), at what dose (e.g., fixed dose versus targeted serum estradiol levels), by what route (i.e., oral, transdermal, transvaginal), and for what length of time. The WHI trials generated important results but raised equally important questions. The risks of oral conjugated estrogens vary, depending on whether they are used with or without MPA, with a more favorable risk profile when estrogen is used alone. The WHI trials appear to support the “timing hypothesis,” that cardiovascular benefits may occur when therapy is initiated near the time of menopause, whereas initiating hormone treatment after 10 or more years of estrogen deficiency may increase risk for cardiovascular events.
The loss of estrogen with menopause appears to be linked with deleterious changes in body composition, including increased central fat accumulation and decreased bone mineral density, which translate long term into increased risk for CVD and fractures. Additionally, the loss of estrogen is associated with hot flashes, decreased sleep quality, vaginal dryness, and worsening of mood disturbances, the sum of which equals decreased quality of life for many women.
In the North American Menopause Society (NAMS) 2017 hormone therapy position statement, hormone therapy is indicated (and approved by the FDA) as first-line therapy for relief of vasomotor symptoms (VMSs) and genitourinary syndrome of menopause (e.g., vaginal atrophy). Hormone therapy is also indicated and FDA approved for use in women with elevated risk for bone loss and fractures, and in those with hypoestrogenism caused by hypogonadism, surgical menopause, or primary ovarian insufficiency. The risks of hormone therapy may differ depending on type, dose, route of administration, duration of use, timing of initiation, and whether a progestin is used. For example, transdermal estradiol appears to be associated with fewer thromboembolic events than oral estrogens. Because the use of continuous conjugated estrogens plus MPA was associated with an increased incidence of invasive breast cancer in the WHI trial (whereas use of conjugated estrogens alone was not), intermittent progesterone may be a better alternative for endometrial protection. The NAMS recommends hormone therapy be individualized with respect to appropriate treatment type and duration to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of therapy. Discontinuation of systemic hormone therapy in women age ≥65 years for safety reasons is not supported by evidence. Decisions to continue hormone therapy use in older women should be judged on an individual basis for quality of life, persistent VMSs, and/or prevention of bone loss and fractures, with appropriate evaluation of risks. Ultimately, a discussion of whether or not to use hormone therapy should be incorporated into recommendations for lifestyle modifications to manage menopausal symptoms and risk for age-associated chronic diseases.