Introduction

Publication Details

Background

Menopause is defined as the permanent cessation of menstruation and ovulation due to ovarian failure. After 12 months of amenorrhea without pathological etiology, menopause is considered “natural” or “spontaneous.” Menopause can also be induced prematurely (before age 40 years) or early (before age 45 years), through medical interventions such as surgery (e.g., bilateral oophorectomy with or without hysterectomy), chemotherapy, or radiation. It occurs naturally between the ages of 42 and 58 years1-3 and is a consequence of reproductive senescence. The average age at onset appears fixed, as it has been unchanged since ancient Greece.4 In the United States, the number of women entering menopause (approximately 2 million per year5) will remain generally stable or even decline as baby boomers age. But given the continued improvement in life expectancy at age 50, the number of menopausal years will increase both for individual women and the population as a whole.

Current terminology describing the stages of menopause were updated in 2012 at the Stages of Reproductive Aging Workshop + 10 (STRAW + 10).6 The STRAW + 10 stages describe early and late phases of menopausal transition and early and late phases of postmenopause. Menopausal transition is defined by variability in menstrual cycle length, followed by periods of amenorrhea lasting 60 days or longer. Early postmenopause lasts 5 to 8 years, from final menstrual period to stabilization of low estradiol levels. Perimenopause is defined as the entire menopausal transition phase, extending into the first 12 months of the early postmenopause stage.6

During menopause, approximately 85 percent of women report experiencing symptoms of varying type and severity.7 Types of symptoms experienced include the following.5

  • Vasomotor symptoms are recurrent, transient episodes of flushing, with intense heat on the face and upper body, sometimes followed by chills. These symptoms can occur while sleeping and can produce intense perspiration (night sweats). Individual hot flushes may last from one to five minutes. After irregular menses, vasomotor symptoms are the second most frequently reported perimenopausal symptom.
  • Increases in sleep disturbances such as insomnia and sleep apnea/hypopnea may occur. Insomnia includes lengthy times to fall asleep, inability to sleep through the night, or inability to resume sleeping when woken prematurely. Sleep apnea symptoms range from slight airflow reductions that cause snoring, to periodic cessation of breathing (apnea).
  • Psychological symptoms such as depressive symptoms, anxiety, and mood disturbances may also occur in perimenopausal and postmenopausal women. The term “depression” may include a depressed mood or an intense adjustment reaction to a life event that may not require treatment. The term may also include clinical depression. If clinical depression is suspected, assessment and treatment are recommended. Symptoms of anxiety may include tension, nervousness, panic, and worry.
  • Urogenital problems such as urinary incontinence and vaginal atrophy may occur. Vaginal atrophy describes vaginal walls that are thin, pale, dry, and sometimes inflamed. These changes cause discomfort and potential trauma during intercourse and during pelvic examinations.
  • Sexual function effects such as dyspareunia (pain during intercourse) and decreased libido are also reported by perimenopausal and postmenopausal women.

Longitudinal studies have shown that during the early postmenopausal period the prevalence of vasomotor symptoms among women ranges from 30 to 80 percent, depressed mood occurs in approximately one-third, and sleep disturbance in more than 40 percent; diminished sexual function and vaginal dryness are also common.8-10 A natural history of symptoms has been described, including the presence, severity, and time since menopause. For example, vasomotor symptoms generally begin 2 years before last menstrual period, peak during the 12 months following last menstrual period, and then diminish over the next 10 years.6, 11 Urogenital atrophy symptoms increase during the late postmenopause stage.6 However, differences in symptoms have been found among different subpopulations of women. In the Penn Ovarian Aging Trial, moderate to severe vasomotor symptoms lasted a median of 10.2 years; black women experienced a longer median duration of vasomotor symptoms, while women with a high body mass index tended to have shorter symptom duration.12 In the Study of Women’s Health Across the Nation, the prevalence of vasomotor symptoms was greater among black and Hispanic women and women with a higher body mass index.13

Menopausal Treatment Strategies

Overview

Estrogens have been a mainstay for treating menopausal symptoms, but are surrounded by controversy. Estrogens were approved by the U.S. Food and Drug Administration (FDA) in 1942 for treating menopausal symptoms, and by 1947, the Physician’s Desk Reference listed more than 50 estrogen preparations approved for treating menopausal symptoms. In 1995, an estimated 37 percent of women aged 50 years or older in the United States reported using menopausal hormone therapy (estrogen with or without progestogen),14 owing in part to the results of observational studies interpreted to support a protective effect for cardiovascular disease. The clinical landscape shifted abruptly in 2002 with the first results from the Women’s Health Initiative (WHI), a randomized comparison of estrogen/progestin versus placebo. Not only was cardiovascular risk increased, but overall harms from the treatment exceeded benefits.15 Although subsequent evaluation of the body of evidence has indicated that interpretations of the results are more complex,16 particularly for the target population included in this review, the consequences for menopausal hormone therapy use in the United States remain uncertain.17

In addition to decreasing estrogen production in menopausal women, the decrease of androgen production is of concern. Androgens affect sexual interest, muscle mass and strength, body mass index, and adipose tissue distribution. Androgens may also affect energy and psychological health. Two major androgens in women are testosterone and dehydroepiandrosterone (DHEA). In women with naturally occurring menopause, there is not a sudden decrease in androgen production, but in women with surgical menopause, testosterone levels decrease by about 50 percent.5 A Cochrane review has reported sufficient evidence to suggest that supplementing estrogen therapy or estrogen/progestogen therapy with testosterone has a beneficial effect on menopausal women experiencing sexual dysfunction.18 DHEA is available without prescription as a dietary supplement, and is, therefore, under limited regulation. The efficacy of DHEA supplements for the treatment of menopausal symptoms has not been established.

Generally prepared for the individual patient, compounding of menopausal hormone therapy combines several hormones and employs nonstandard routes of administration.19 Compounded hormones are claimed to be biochemically similar or identical to endogenous hormones. Compounded preparations typically contain estriol and can have variable potency.20 Growing interest in compounded hormones is undisputed; evidence from surveys of pharmacists, practitioners, and women suggests a growing market for and belief in their effectiveness.21, 22 In 2003, approximately 30 million prescriptions for compounded products were filled.23 The products are heavily marketed, currently a $1 billion industry and growing.24

While menopausal hormone therapy can relieve symptoms, concerns about potential risks (especially cardiovascular disease and uterine and breast cancer) provide reason to consider other agents. Both nonhormone prescription medications and nonprescription agents including complementary and alternative medicine (CAM) therapies have been studied in comparison with menopausal hormone therapy or placebo. These studies focus primarily on the relief of vasomotor symptoms.25 Nonhormone prescription therapies include selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI), eszopiclone, clonidine, methyldopa, gabapentin; biologic CAM therapies include isoflavones, red clover (Trifolium pratense), black cohosh (Cimicifuga racemosa), St. John’s wort (Hypericum perforatum), ginseng, flax seed, vitamin E, dong quai (Angelica sinensis), and DHEA. Postulated mechanisms for SSRIs and SNRIs include central effects on serotonin, dopamine, or norepinephrine,26 while the potential benefit of isoflavones is thought to be mediated through their affinity for estrogen receptors. In the Study of Women’s Health Across the Nation, depending on ethnicity, 20 to 70 percent of participants reported using some form of CAM therapy during the menopausal transition phase.27

Guidelines and Society Statements

The principal uncertainty for nonhormone therapies is effectiveness, whereas for hormone therapies it is the balance of benefits and harms. In May 2012, the U.S. Preventive Services Task Force (USPSTF) issued an update to their 2005 guideline titled Hormone Replacement Therapy for the Prevention of Chronic Conditions in Postmenopausal Women, in which the use of hormones for the prevention of chronic conditions was not recommended. This updated systematic review included research published through November 2011, but the report did not consider treatment of menopausal symptoms.28

The 2010 North American Menopause Society (NAMS) position statement on menopausal hormone therapy concluded, “Recent data support the initiation of [menopausal hormone therapy] around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal [hormone therapy] is favorable for women who initiate [hormone therapy] close to menopause but decreases in older women and with [greater] time-since-menopause in previously untreated women.”29

The 2007 International Menopause Society (IMS) recommendations state, “The safety of [menopausal hormone therapy] largely depends on age. Women younger than 60 years old should not be concerned about the safety profile of [menopausal hormone therapy]. New data and reanalyses of older studies by women’s age show that, for most women, the potential benefits of menopausal hormone therapy given for a clear indication are many and the risks are few when initiated within a few years of menopause.”30 Neither the NAMS position statement nor the IMS recommendations were accompanied by systematic reviews, yet both express considerable certainty and are somewhat at odds with trends in menopausal hormone therapy use.17

The Endocrine Society recently performed an extensive review of evidence surrounding postmenopausal hormone therapy, published as a scientific statement.31 Efforts to systematically review and synthesize the literature were described, although methods used in the review (e.g., search strategies and the process for rating evidence) were not detailed. Reviewers graded the quality of the evidence supporting use of menopausal hormone therapy as “high” for ameliorating vasomotor symptoms and vaginal atrophy, preventing bone loss, decreasing colon cancer risk, and increasing the risk of venous thromboembolism and gallbladder disease.

Position statements on compounded therapies have also been issued. The NAMS does not generally recommend compounded combined hormone therapy and suggests that compounded hormone products include a patient package insert identical to that required for products that have government approval. The NAMS states that “in the absence of efficacy and safety data for bioidentical [compounded] hormone therapy, the generalized benefit-risk ratio data of commercially available hormone therapy products should apply equally to bioidentical [compounded] hormone therapy.”19 Similar views are held by American College of Obstetricians and Gynecologists (ACOG), The Endocrine Society, and the American Association of Clinical Endocrinologists (AACE). ACOG states that in addition to having the same safety issues as those associated with FDA-approved menopausal hormone therapy, compounded hormones may have additional risks intrinsic to compounding.32 The FDA maintains that while pharmacists engaging in traditional compounding provide a valuable service, anyone receiving compounded hormones should discuss options with their health-care provider to determine if compounded drugs are the best option for their medical needs.33

Challenges in Synthesizing the Evidence

From the perspectives of systematic review and evidence synthesis, there are a number of challenges in comparing different hormone therapies and comparing those therapies to alternatives:

  • Population: Trial populations vary by factors such as age, ethnicity, time since menopause, length of time on hormone replacement therapy, BMI, and uterine status. For example, in a single trial, women with and without a uterus may be offered different treatment regimens.
  • Intervention: The array of hormone and nonhormone therapies is broad and includes a number of biologic CAM and prescription agents, making synthesis difficult. Hormone therapies vary by preparation, type, and administration route. Compounded hormones are not standardized.
  • Outcomes: There are numerous categories of menopausal outcomes: psychological, vasomotor, sexual function, sleep disturbances, and overall quality of life. Each of these categories can be measured by a variety of standardized scales, making synthesis challenging. Also, these outcomes are self-reported, and individuals assess levels of importance and severity of symptoms differently.
  • Timing: Some harms are not immediately evident (e.g., breast cancer), and some benefits are not immediately evident (e.g., prevention of osteoporosis and fractures). Long followup times are necessary to adequately determine benefits and harms from these therapies.

Two large-hormone replacement therapy trials exemplify the complexities described above when collecting evidence for a systematic review on this topic. The WHI, which is a primary evidence base for harms from hormone replacement therapy, had a treatment population that overlaps but differs from the target population in this review. The WHI hormone trials excluded women with severe menopausal symptoms and enrolled primarily women older than those recently menopausal. These population characteristics of the WHI trials are relevant when attempting to interpret the results. A more recent report from the WHI observational trial34 found women experiencing early vasomotor symptoms were at the lowest risk of cardiovascular disease and cardiovascular events. Another large trial with combined menopausal hormone therapy,35 the Women’s International Trial of Long Duration Oestrogen after Menopause [WISDOM], was prematurely closed because of the findings of the WHI trial, resulting in a trial with only one year of followup.

Objectives

For an individual menopausal woman considering hormonal or nonhormonal therapies, the questions of interest are: Given the presence of menopausal symptoms, what is the balance of benefits and harms of these therapies? Does the timing and duration of these therapies affect the balance? Accordingly, the objectives of this review include: systematically reviewing and synthesizing evidence evaluating the comparative effectiveness of treatments for menopausal symptoms, potential benefits other than symptom relief, and potential harms.

Population(s), Interventions, Comparators, Outcomes, Timing, and Setting

Population(s)

Women experiencing symptoms accompanying natural menopause (during perimenopausal or postmenopausal periods) or surgically induced menopause (during the postmenopausal period).

Interventions

Three categories of interventions are included in the report: hormone therapies, nonhormone prescription therapies, and nonprescription therapies:

  • Hormone therapies including estrogen therapy and estrogen/progestogen (or estrogen/androgen) therapy administered by oral, transdermal, nasal, or vaginal route; combined estrogen-progestogen and progesterone-only contraceptives; compounded menopausal hormone therapy, often referred to as “bioidentical hormones”
  • Nonhormone prescription therapies including SSRI/SNRIs, eszopiclone, clonidine, methyldopa, and gabapentin
  • Nonprescription therapies including isoflavones, red clover, black cohosh, St. John’s wort, ginseng, flax seed, vitamin E, dong quai, and DHEA

Comparators

Placebo or direct comparison between therapies, such as varying hormone dose and formulation.

Outcomes

  • For Key Question 1 (KQ1) and Key Question 4 (KQ4):
  • Final outcomes are menopausal symptom-related:
    • Vasomotor symptoms
    • Sleep disturbance
    • Psychological symptoms
    • Urogenital atrophy
    • Sexual function
    • Quality of life
  • For Key Question 2 (KQ2) and Key Question 3 (KQ3):
  • Final outcomes are other benefits and harms:
    • Coronary heart disease
    • Stroke
    • Venous thromboembolism
    • Breast cancer
    • Endometrial cancer
    • Ovarian cancer
    • Colorectal cancer
    • Gallbladder disease
    • Osteoporotic fractures
    • Agent-specific adverse events

Timing

For KQ1 and KQ4, at least 12 weeks of followup for adequate assessment of hormone and nonprescription treatment effects is required for inclusion. For centrally acting agents (SSRI, SNRI, and gabapentin) minimum trial duration will be 4 weeks. This is based on evidence that efficacy in treating vasomotor symptoms with these agents is demonstrable by 4 to 8 weeks—and translates into similar efficacy at 12 weeks.36 For KQ2 and KQ3, longitudinal studies on colorectal cancer, breast cancer, and ovarian cancer require a followup of 5 years or greater for inclusion. Longitudinal studies on coronary heart disease, stroke, venous thromboembolism, endometrial cancer, gallbladder disease, and osteoporotic fractures require a followup of one year or greater for inclusion.

Setting

Primary care and community settings

Key Questions

Key Question 1. What is the comparative effectiveness of different treatments for reducing symptoms of menopause (vasomotor symptoms, sleep disturbance, psychological symptoms, urogenital atrophy, and sexual function) and for improving quality of life? Individual agents will be compared to the extent permitted by the evidence.

Treatments of interest include:

  • Hormone therapies
    • Oral estrogen alone or combined with progestogen (or androgen)
    • Transdermal estrogen or combined with progestogen
    • Vaginal estrogen
    • Combined estrogen-progestogen and progesterone-only contraceptives (for women desiring contraception)
    • Compounded menopausal hormone therapy

Evidence evaluating hormone therapies will be considered separately for women with and without a uterus. Women with breast cancer will be excluded.

  • Nonhormone therapies
    • Prescription
      • SSRI/SNRIs
      • Eszopiclone
      • Clonidine
      • Methyldopa
      • Gabapentin
    • Nonprescription, complementary and alternative therapies
      • Isoflavones, including red clover (Trifolium pratense)
      • Black cohosh (Cimicifuga racemosa)
      • St. John’s wort (Hypericum perforatum)
      • Ginseng
      • Flax seed
      • Vitamin E
      • Dong quai (Angelica sinensis)
      • Dehydroepiandrosterone

Key Question 2. What are the effects of menopausal hormone therapy preparations on coronary heart disease, stroke, or venous thromboembolism; gallbladder disease; osteoporotic fractures; or endometrial, breast, colorectal, or ovarian cancers? Exposure will be examined according to duration of use and initiation relative to age and onset of menopause. (For women desiring contraception, combined estrogen-progestogen and progesterone-only contraceptives are included.)

Key Question 3. What are the effects of nonhormone therapy preparations on coronary heart disease, stroke, or venous thromboembolism; gallbladder disease; osteoporotic fractures; or endometrial, breast, colorectal, or ovarian cancer? Exposure will be examined according to duration of use and initiation relative to age and onset of menopause. What are the significant agent-specific harms/adverse effects of nonhormone therapies?

Key Question 4. Does effectiveness and adverse effects vary among subgroups of participants defined by demographics, symptom severity, other medications, and comorbidities or according to agent, preparation, or dose?

Analytic Framework

Figure 1 depicts the potential impact of both hormonal and nonhormonal treatments among women with menopausal symptoms. KQ1 and KQ4 illustrate how hormone and nonhormone therapies for menopausal symptoms may improve quality of life as well as reduce the occurrence or severity of the following symptoms: vasomotor symptoms, sleep disturbance, sexual function, urogenital atrophy, quality of life, and psychological symptoms. Other benefits of these treatments may include the prevention of osteoporotic fractures and colorectal cancer, as represented by the straight line of KQ2 and KQ3. The curved line of KQ2 and KQ3 represent potential consequential adverse effects among women using hormone and nonhormone therapies. These adverse effects include coronary heart disease, stroke, venous thromboembolism, breast cancer, endometrial cancer, ovarian cancer, and gallbladder disease.

Figure 1 is the analytical framework for the project. For women experiencing menopausal symptoms, whether naturally or surgically-induced, what are the potential impacts of hormonal and nonhormonal treatments? KQ1 and KQ4 represent how hormone and nonhormone therapies may improve: vasomotor symptoms, quality of life, sleep disturbance, sexual function, urogenital atrophy, and psychological symptoms. Other potential benefits of these treatments may include the prevention of osteoporotic fractures and colorectal cancer, as represented by the straight line of KQ2 and KQ3. The curved line of KQ2 and KQ3 represent potential long term adverse effects from using these hormone and nonhormone therapies. Adverse effects include: coronary heart disease, stroke, and venous thromboembolic events; breast, endometrial, and ovarian cancer; and gall bladder disease.

Figure 1

Analytic framework. a Excludes women with breast cancer or receiving tamoxifen.