Final Research Plan
Hormone Therapy in Postmenopausal Persons: Primary Prevention of Chronic Conditions
May 27, 2021
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
a Definitions of perimenopausal and postmenopausal persons are based on STRAW+ 10 criteria.
Abbreviation: KQ=key question; STRAW+ 10=Stages of Reproductive Aging Workshop+ 10.
- What are the benefits of menopausal hormone therapy (HT) when used for the primary prevention of chronic conditions?
- What are the harms of menopausal HT when used for the primary prevention of chronic conditions?
- Do the benefits and harms of menopausal HT when used for the primary prevention of chronic conditions differ by subgroup (e.g., by race/ethnicity; persons with premature menopause; persons with surgical menopause; age during HT use; duration of use; type, dose, and mode of delivery of HT; and comorbid condition) or by timing of intervention (initiation of HT during perimenopause vs. postmenopause)?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What is the average treatment duration in persons who start HT for menopausal symptoms?
- Does the use of HT vary by subgroup (e.g., by race/ethnicity, age, or comorbid condition)?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria apply to all of the key questions. Findings related to the benefits and harms of estrogen alone and of combination estrogen and progestogen will be synthesized and reported separately.
Table 1. Inclusion and Exclusion Criteria
|Interventions||Systemic therapy with estrogen-only formulations or combinations with progestogens (progesterone or progestin) for prevention of chronic conditions. Medications are FDA approved and available for use in the United States. See Table 2.||Localized (nonsystemic) treatments such as rings, creams, or gels; contraceptives; other hormones; treatments of menopausal symptoms such as over-the-counter preparations or compounded bioidentical therapies that are not FDA-approved|
|Control interventions||Placebo, no treatment||Active comparator|
||Any outcomes that are not health outcomes of chronic conditions associated with HT; intermediate outcomes, such as bone density and cholesterol level|
|Duration of intervention||≥1 year of treatment||Less than 1 year of treatment|
|Publication language||English||Non-English language|
|Study design||All outcomes:
For outcomes or subgroups with no evidence from trials or systematic reviews
|All other study designs|
|Publication type||Published or unpublished original research||Nonsystematic review article, letter, editorial, results reported elsewhere, no original data|
|Geography||U.S. adult population or comparable populations (categorized as “Very High” using the Human Development Index, as defined by the United Nations Development Programme)||Not comparable or applicable to U.S. adult population|
|Setting||Primary care or primary care–like settings||Inpatient facilities, nursing homes, hormone specialist offices|
*The Centers for Disease Control and Prevention defines chronic diseases as conditions that last 1 or more years and require ongoing medical attention, limit activities of daily living, or both. The following are classified as chronic diseases: heart disease, cancer, chronic lung disease, stroke, Alzheimer’s disease, diabetes, and chronic kidney disease. Source: Centers for Disease Control and Prevention. About Chronic Diseases. https://www.cdc.gov/chronicdisease/about/index.htm. Accessed May 7, 2021.
Table 2. List of Included Interventions, Extracted From FDA List of Approved Hormone Therapy*
|Category of Hormone Therapy and Generic Name||Brand Name||Product Type||Dosage†|
|Estradiol‡||Alora||Patch||0.025–0.1 mg worn for 24 hours twice weekly|
|Synthetic conjugated estrogens||Cenestin||Pill||0.3–1.25 mg/day|
|Estradiol‡||Climara||Patch||0.025–0.1 mg worn for 24 hours once weekly|
|Estradiol valerate||Delestrogen||Injection||10/20/40 mg/mL/month|
|Estradiol‡||Estraderm||Patch||0.05–0.1 mg continuously or cyclically§|
|Estradiol‡||Menostar||Patch||0.014 mg worn for 24 hours once weekly|
|Estradiol‡||Minivelle||Patch||0.025–0.1 mg worn for 24 hours twice weekly|
|Micronized progesterone||Prometrium||Pill||0.625 mg/day|
|Medroxyprogesterone acetate||Provera||Pill||100–200 mg/day|
|Estradiol‡||Vivelle-Dot||Patch||0.025–0.1 mg worn for 24 hours twice weekly|
|Estradiol acetate‡||Femtrace||Pill||0.45–1.8 mg/day|
|Esterifield estrogen‡||Menest||Pill||0.3–1.25 mg/day cyclically§|
|Conjugated estrogens¶||Premarin||Pill, injection||0.3 mg/day cyclically,§ single 25-mg injection|
|Synthetic conjugated estrogens#||Enjuvia||Pill||0.3 mg/day|
|Conjugated estrogen¶/bazedoxifene||Duavee||Pill||Conjugated estrogen 0.45 mg/day with bazedoxifene 20 mg/day|
|Combination Estrogen Plus Progestin Formulations|
|Estradiol‡ + drospirenone**||Angeliq||Pill||Drospirenone 0.25–0.5 mg/day with estradiol 0.5–1.0 mg/day|
|Estradiol‡ + norethindrone acetate#||Activella||Pill||Estradiol 0.5–1.0 mg/day with norethindrone 0.1 mg/day|
|Estradiol‡ + norgestimate**||Prefest||Pill||Repeat estradiol 1 mg/day for 3 days followed by estradiol 1 mg/day with norgestimate 0.09 mg/day for 3 days|
|Estradiol‡ + levonorgestrel**||Climara Pro||Patch||Estradiol 0.045 mg with levonorgestrel 0.015 mg worn for 24 hours once weekly|
|Estradiol‡ + norethindrone acetate**||Combipatch||Patch||Estradiol 0.05 mg with norethindrone 0.14–0.25 mg worn for 24 hours once weekly|
|Conjugated estrogene + medroxyprogesterone acetate**||Prempro||Pill||Conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 5 mg/day|
|Ethinyl estradiol‡ + norethindrone acetate#||Femhrt||Pill||Ethinyl estradiol 0.0025 mg/day with norethindrone acetate 0.500 mg/day|
* Source: U.S. Food and Drug Administration. Menopause: Medicines to Help You. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you. Accessed May 7, 2021.
† Dosages are based on the package inserts for the brand name formulations.
? Estradiol can be from natural sources or prepared synthetically.
§ Cyclically means “within a cycle” (e.g., repeat 3 weeks of treatment and 1 week off).
? Natural estrogenic substance prepared from purified crystalline estrone.
¶ Conjugated estrogens, such as conjugated equine estrogens, are derived wholly or partially from the urine of pregnant mares or synthetic estrone and equilin.
# Synthetic conjugated estrogens are prepared using plant sources, such as yams and soy, and use only synthetic resources.
** Synthetic progestin.
Abbreviation: FDA=Food and Drug Administration.
The draft Research Plan was posted for public comment on the USPSTF website from February 18, 2021, to March 17, 2021. In response to the comments, the USPSTF clarified that findings related to the benefits and harms of estrogen alone and of combination estrogen and progestogen will be synthesized and reported separately. Several comments requested that the USPSTF include intermediate outcomes, such as cholesterol levels and bone density, and prevention of vasomotor symptoms and genitourinary syndrome of menopause; these outcomes are considered to be outside the scope of this review, which is focused on primary prevention of chronic conditions. The USPSTF clarified the definition of chronic diseases in the Research Plan. Several comments requested that the USPSTF include a broader range of interventions, such as nonsystemic treatments, progesterone only therapy, androgen therapy, and testosterone therapy; nonsystemic treatments are not expected to affect health beyond the genitourinary system (e.g., systemic delivery would be necessary to affect risk for cardiovascular disease), and progesterone only therapy, androgen therapy, and testosterone therapy are not approved as HT in postmenopausal persons. This review also limits HT to estrogen alone or combination estrogen and progestogen because only these formulations are approved for HT in postmenopausal persons.