in progress

Draft Research Plan

Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons

February 18, 2021

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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 progestin 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 women are based on STRAW+10 criteria. From the population of interest there is an arrow going across to intermediate outcomes and an arrow going from intermediate outcomes to improved health outcomes, which is reduction in mortality. There is also an arrow pointing down to adverse effects. 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; women with premature menopause; women with 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 women are based on STRAW+ 10 criteria. 

Abbreviations: KQ=key question; STRAW+=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 differ by subgroup (e.g., by race/ethnicity; women with premature menopause; women 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 women who start HT for menopausal symptoms?
  2. Does the use of HT vary by subgroup?

The Proposed 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.

  Include Exclude
Population
  • Generally healthy perimenopausal and postmenopausal women eligible for menopausal HT
  • Women with and without menopausal symptoms will be included if the focus of the analysis is on the prevention of chronic conditions
  • Animals; men; premenopausal women; postmenopausal women 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; or populations that are not applicable to U.S. primary care
  • Postmenopausal women who use HT for secondary prevention of chronic conditions
Interventions Systemic therapy with estrogen-only formulations or combinations with 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 or gels, contraceptives, other hormones, or 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 nonsmall 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; 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 women)
 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 (i.e., those categorized as “Very High” on the Human Development Index, as defined by the United Nations Development Programme) Not comparable or applicable to U.S. adult population
Date of search January 2011 onward Before January 2011
Setting Primary care or primary care–like settings Inpatient facilities, nursing homes, hormone specialist offices

Abbreviations: FDA=Food and Drug Administration; HT=hormone therapy; RCT=randomized, controlled trial; U.S.=United States.

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 0.025–0.1 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
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 January 28, 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.