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.

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This figure is an analytic framework depicting the key questions (KQs) within the context of the populations, interventions, comparisons, outcomes, time frames, and settings (PICOTS) relative to the benefits and harms of the primary prevention of chronic conditions with estrogen or combination estrogen and progestogen menopausal hormone therapy (HT). This figure illustrates the HT pathway for the population of interest, namely perimenopausal and postmenopausal women eligible for HT. The definitions of perimenopausal and postmenopausal persons are based on STRAW+10 criteria. From the population of interest listed on the left side of the figure, there is an arrow going across to intermediate outcomes in the middle of the figure and an arrow going from intermediate outcomes to improved health outcomes, reduction in mortality on the right side of the figure. There is also an arrow pointing down to adverse effects from the arrow connecting perimenopausal and postmenopausal persons and intermediate outcomes. There are two overarching questions for the review that span the entire analytic framework. The first (KQ 1) examines the benefits that may result from use of HT when used for the primary prevention of chronic conditions and the second (KQ 3) evaluates whether those benefits differ by subgroups (including race or ethnicity; persons with premature menopause; surgical menopause; age of use; duration of use, type, dose, and mode of hormone delivery; and comorbid conditions) or by timing of intervention (initiation of HT during perimenopause or postmenopause). There are two questions for the review that apply to adverse events. The first (KQ 2) examines the harms associated with HT when used for the primary prevention of chronic conditions and the second (KQ3) evaluates whether those harms differ by subgroups or by timing of intervention.

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.

  1. What are the benefits of menopausal hormone therapy (HT) when used for the primary prevention of chronic conditions?
  2. What are the harms of menopausal HT when used for the primary prevention of chronic conditions?
  3. 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.

  1. What is the average treatment duration in persons who start HT for menopausal symptoms?
  2. 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

  Include Exclude
Population
  • Generally healthy perimenopausal and postmenopausal persons eligible for menopausal HT
  • Persons with and without menopausal symptoms will be included if the focus of the analysis is on the primary prevention of chronic conditions
  • Animals; males; premenopausal persons; postmenopausal persons with contraindications for HT use such as history of breast cancer, coronary heart disease, a previous venous thromboembolic event or stroke, active liver disease, or those at high risk for these complications; populations not applicable to U.S. primary care
  • Postmenopausal persons who use HT for secondary prevention of chronic conditions
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
Outcomes
  • Overall mortality
  • Disease-specific mortality (if related to chronic conditions* of interest)
  • Coronary heart disease
  • Stroke
  • Thromboembolism
  • Cancer (breast, colorectal, endometrial, ovarian, and non-small cell lung)
  • Cholecystitis
  • Fractures
  • Cognition
  • Quality of life (if related to chronic conditions of interest)
  • Functional capacity
  • Urinary incontinence
  • Diabetes
 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:
  • RCTs
  • Controlled clinical trials
  • Systematic reviews

For outcomes or subgroups with no evidence from trials or systematic reviews

  • Large cohort studies (more than 10,000 persons)
 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†
Estrogen-Only Formulations
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 Esclim Patch 0.025–0.1 mg/day
Estradiol‡ Estrace Pill 0.5–2 mg/day
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
Estropipate Ortho-Est Pill 0.625 mg/day
Micronized progesterone Prometrium Pill 0.625 mg/day
Medroxyprogesterone acetate Provera Pill 100–200 mg/day
Estradiol‡ Vivelle Patch 0.0375–0.1 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§
Estropipateǁ Ogen Pill 0.75–3 mg/day
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.
ǂ 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).
ǁ 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.