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Hormone Therapy for the Management of Menopause Symptoms
JOGNN CNE Continuing Nursing Education (CNE) Credit A total of 1.5 contact hours may be earned as CNE credit for reading “Hormone Therapy for the Management of Menopause Symptoms” and for completing an online posttest and evaluation. AWHONN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. AWHONN holds a California BRN number, California CNE Provider #CEP580
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Hormone Therapy for the Management of Menopause Symptoms Heidi Collins Fantasia and Melissa A. Sutherland
ABSTRACT Many women will undergo menopause without incident, but others will experience bothersome effects resulting from declining estrogen levels. Vasomotor symptoms, which manifest as intense feelings of warmth, flushing, and perspiration, are the most common symptoms for which women seek treatment. Hormone therapy is indicated for the relief of vasomotor symptoms related to menopause. We review current Food Drug Administration-approved options for hormone therapy and discuss implications for practice and patient education.
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Keywords menopause hormone therapy vasomotor symptoms estrogen progesterone
Correspondence Heidi Collins Fantasia, PhD, RN, WHNP-BC, University of Massachusetts Lowell, College of Health Sciences, School of Nursing, 113 Wilder Street, Lowell, MA 01854. [email protected]
The authors and planners for this activity report no conflict of interest or relevant financial relationships. The article includes no discussion of off-label drug or device use. No commercial support was received for this educational activity. Heidi Collins Fantasia, PhD, RN, WHNP-BC, is an assistant professor in the College of Health Sciences, School of Nursing at the University of Massachusetts Lowell and a nurse practitioner for Health Quarters, Beverly, MA.
ccording to the U.S. Census Bureau demographic profile, in 2010 there were almost 23 million women in the United States between the ages of 45 and 54 (U.S. Census Bureau, 2010), and the average age of natural menopause in the United States is 51 (North American Menopause Society [NAMS], 2013). This physiologic transition is a universal event that affects all women and marks the end of reproductive capability. It is influenced by a myriad of factors, including genetics, environment, diet, weight, smoking, and overall health status (NAMS, 2010).
A
Vasomotor instability that occurs as a result of declining estrogen levels can have a negative impact on the quality of life and is often the main symptom of menopause that causes women to seek treatment (Avis et al., 2009; Burleson, Todd, & Trevathan, 2010; Hess et al., 2012). Hormone therapy is approved by the Food and Drug Administration (FDA) as the most effective treatment for vasomotor symptoms of menopause (NAMS, 2012) but is currently underused due to concerns regarding potential side effects, including risk for breast cancer and venous thromboembolism (Hersh, Stefanick, & Stafford, 2004; Neal-Perry & Pal, 2011; Newton et al., 2010). Patients and health care providers may overestimate the potential for harm and underestimate the potential benefits of hormone therapy (HT) (Rees, 2005). In this article we review current FDA-approved hormonal pharmacologic options for women experiencing symptoms of menopause, discuss the controversy
surrounding HT, and discuss clinical implications for nurses who work with women experiencing the transition through menopause.
Diagnosis of Menopause Menopause can only be diagnosed retrospectively, and menstrual cycle details provided by women represent the most important information to determine menopause status (Harlow et al., 2012). Menopause is defined as occurring after 12 months of amenorrhea that results from the loss of ovarian follicular activity that cannot be attributed to another physiologic or pathologic cause (NAMS, 2010; National Institutes of Health [NIH], 2005; World Health Organization [WHO], 1996). The years preceding the permanent cessation of menses are characterized by endocrine changes that affect menstrual cycle frequency, amount, and duration (NAMS, 2010). Although physiologic signs of hormone fluctuation during menopause may occur, no one specific laboratory or diagnostic test to determine if a patient is menopausal exists. Hormonal biomarker assays, especially for follicle stimulating hormone (FSH), are not reliable due to lack of international standardization and wide variability among women (Harlow et al., 2012; NAMS, 2010). Elevated FSH levels > 30 IU/ml are indicative of increasing ovarian follicular atresia, but laboratory measurements cannot confirm menopause (Harlow et al., 2012; O’Neill & Eden, 2012).
(Continued)
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Symptoms of Menopause Vasomotor Instability Vasomotor instability (or hot flashes), a primary symptom of menopause, includes a sudden feeling of intense heat accompanied by perspiration and flushing (NIH, 2005) and typically lasts less than 10 minutes. Vasomotor instability may also be associated with symptoms of anxiety, palpitations, and sleep disturbances. Although the prevalence of vasomotor symptoms varies across racial and ethnic backgrounds, more than 50% of women report vasomotor symptoms at some point during menopause (O’Neill & Eden, 2012).
Hypoestrogenic Changes Declining estrogen levels are associated with urogenital atrophy. Vulvar and vaginal symptoms may include dryness, pruritus, burning, and pain, especially with intercourse (Gorodeski, 2012). Although the natural aging process is a contributing factor to urogenital symptoms, estrogen deficiency has been established as the main etiology of vaginal epithelial thinning and atrophic vaginitis (Gorodeski, 2012; O’Neill & Eden, 2012).
The Women’s Health Initiative Hormone Trials The Women’s Health Initiative (WHI) clinical trials were parallel, multicenter, randomized, controlled primary prevention trials designed to investigate the effects of hormone therapy (HT) on major health issues in postmenopausal women such as coronary artery disease (CAD). The primary adverse outcome of the research trials was invasive breast cancer (Rossouw et al., 2002; Anderson et al., 2004). Researchers studied multiple foci and in one arm compared daily estrogen (conjugated equine estrogen [CEE] 0.625 mg) plus progesterone (medroxyprogesterone acetate [MPA] 2.5mg) with a placebo for the primary prevention of cardiovascular disease among postmenopausal women. A total of 16,608 healthy, postmenopausal women with an intact uterus and a baseline age of 50 to 79 were enrolled between 1993 and 1998. In May of 2002 after 5 out of 8 years of anticipated follow-up, the estrogen plus progesterone arm was halted by the study’s Data Safety Monitoring Board after unanticipated risks were judged to outweigh potential benefits. Compared to women receiving placebo, women in the estrogen/progesterone group had increased risks of breast cancer, stroke, pulmonary embolism, and myocardial infarction (Rossouw et al., 2002).
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The early termination of the estrogen plus progesterone and estrogen only arms of the Women’s Health Initiative has shaped the pharmacologic treatment of menopause symptoms.
The estrogen-only arm of the study was also terminated early. In this portion of the WHI, 10,739 postmenopausal women age 50 to 70 who had undergone a hysterectomy were enrolled. These women received daily estrogen (0.625 mg CEE) without added progesterone. Early termination occurred when investigators reported that when compared with placebo, the use of daily estrogen increased the risk of stroke and did not reduce the incidence of CAD (Anderson et al., 2004).
Rethinking WHI Study Results The early termination of both arms of the WHI has shaped the subsequent pharmacologic treatment of menopause symptoms. Prior to the publication of the WHI results, HT was most commonly prescribed to control the vasomotor symptoms of menopause that are experienced by more than one half of perimenopausal and postmenopausal women (Santen et al., 2010). When the initial research results were published, use of HT declined significantly as a result of patient and provider concerns and fear of potential liability if adverse events were to occur (Hersh et al., 2004; Neal-Perry & Pal, 2011; Newton et al., 2010). Since the initial publication of the WHI results, the original research conclusions regarding risks of adverse events have been questioned and limitations closely examined (Utian, 2012). Three limitations often cited include the age of the sample, the determination of relative risk, and the formulation of the HT. The age range for inclusion in the WHI trials was 50 to 79, and the mean age was 63 (Rossouw et al., 2002). The age range of almost 20 years was necessary due to the large numbers of participants needed to adequately power the study and achieve statistical significance for the small number of predicted adverse outcomes (Anderson et al., 2004; Rossouw et al., 2002). However, the average age of participants (63) was more than 10 years older than the age at which women would typically be offered HT for symptoms of menopause. As women age their risks for cardiovascular incidents such as myocardial infarction and thromboembolic events increase. Therefore, it is challenging to determine whether the adverse cardiovascular events that
Melissa A. Sutherland, PhD, FNP-BC, is an assistant professor at the William F. Connell School of Nursing, Boston College, Chestnut Hill, MA and a certified family nurse practitioner.
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occurred among participants in the WHI trials were associated with the addition of HT, the natural aging process, or both (Utian, 2012). Another critique is that the researchers overstated their conclusions related to the risk of adverse events. The results were interpreted in terms of relative risk, that is, the risk of an adverse event as a result of receiving the HT intervention compared to not receiving the intervention. Researchers who have reviewed the conclusions of the WHI study have questioned whether outcomes should have instead been interpreted in terms of absolute risk, that is, the individual participant’s baseline risk of having an adverse event prior to the intervention and reporting the risk post-intervention (Clark, 2006; Utian, 2012). The last critique relates to the HT formulations that were used. The WHI researchers only evaluated the use of oral HT preparations based on one formulation and dose of estrogen (0.625 mg CEE) and progesterone (2.5mg MPA). The researchers acknowledged this limitation and the fact that the results may not apply to HT delivered by another route, dose, or different hormonal compound (Anderson et al., 2004; Rossouw et al., 2002).
Current Hormone Therapy Recommendations Prior to the publication of the WHI results, HT was routinely prescribed not only for the control of vasomotor symptoms, but also for the prevention of chronic health conditions (Nelson, Walker, Zakher, & Mitchell, 2012). Currently, HT should be considered only to treat menopausal symptoms (primarily vasomotor symptoms) that negatively affect quality of life (NAMS, 2012). It should not be prescribed to prevent chronic conditions such as cardiovascular disease, dementia, osteoporosis, and colorectal cancer. Additionally, evidence suggests that the timing of HT initiation may be important to consider when counseling women who are considering HT for symptoms of menopause (Harman et al., 2011). In women who have been menopausal for less than ten years (typically in the age range of 50–59), short-term use of HT has not been associated with an increase in mortality or heart disease (Harman et al., 2011; Rossouw et al., 2007; Stram et al., 2011). Currently, shortterm use is defined as 5 years (Rossouw, Manson, Kaunitz, & Anderson, 2013).
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FDA-Approved Pharmacologic Options The NAMS supports the use of FDA-approved HT as the most effective treatment of moderate to severe menopause related vasomotor symptoms in women without contraindications to estrogen or estrogen/progesterone (NAMS, 2012). Because no randomized controlled trials (RCTs) have been conducted to compare hormone dosage and/or route of administration, the NAMS recommends that the lowest dose of FDA approved estrogen or estrogen plus progesterone that is effective for treating and controlling symptoms should be used for the shortest amount of time (NAMS, 2012). Route of delivery (oral, transdermal, vaginal) should be determined after an individualized discussion with each woman and reflect her lifestyle and preferences. Individual oral, transdermal, and vaginal preparations are listed in Tables 1 through 4.
Oral HT preparations Oral HT is available as either estrogen-only or estrogen-plus-progesterone preparations. Systemic oral estrogen is most often prescribed to manage vasomotor symptoms. Individual preparations and doses are listed in Tables 1 and 2. Several important factors should be considered prior to prescribing oral HT. For women with a uterus, addition of a progestin is recommended to reduce the risk of endometrial hyperplasia from exposure to unopposed estrogen. Additional progesterone can be added in either a cyclic or continuous fashion. Progesterone that is taken on a continuous, daily basis with estrogen will avoid a monthly withdrawal bleed that occurs when progesterone is taken cyclically in either the first or second one half of the month. Oral administration of estrogen has a greater effect on the liver due to the first-pass effect. To overcome the effects of hepatic metabolism, oral HT must be given in higher doses than transdermal HT to achieve a serum concentration that is great enough to relieve vasomotor symptoms (Kopper, Gudeman, & Thompson, 2008). Oral estrogen products increase C-reactive protein (CRP) that is associated with inflammation and tissue damage and may lead to atherosclerotic cardiovascular disease, especially with long-term use of more than 5 years (Goodman, 2012). Oral estrogen has a favorable effect on lipid profiles through an increase in high-density lipoprotein (HDL) and a decrease in low-density lipoprotein (LDL) but
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Table 1: Oral Estrogen Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage (mg/day)
Conjugated estrogens
Premarin
0.3, 0.45,∗ 0.625, 0.9, 1.25
Synthetic conjugated estrogens, A
Cenestin
0.3. 0.45, 0.625, 0.9, 1.25
Synthetic conjugated estrogens, B
Enjuvia
0.3, 0.45, 0.625, 0.9, 1.25
Esterified estrogens
Menest
0.3, 0.625, 1.25, 2.5
17β-estradiol
Estrace,
0.5, 1.0, 2.0
Various generics
0.5, 1.0, 2.0
Estradiol acetate
Femtrace
0.45, 0.9, 1.8
Estropipate
Ortho-Est
0.625 (0.75 estropipate), 1.25 (1.5), 2.5 (3.0), 5.0 (6.0)
Ogen
0.625 (0.75 estropipate), 1.25 (1.5), 2.5 (3.0)
Various generics
0.625 (0.75), 1.5 (3.0), 5.0 (6.0)
Note. Adapted with permission from the North American Menopause Society (NAMS).
increases triglyceride levels, which is an independent risk factor for stroke (Goodman, 2012). Oral estrogen preparations are available in a wide range of doses, and HT can be tailored based upon the severity of vasomotor symptoms. The health risks of HT discovered in the WHI trials were associated with a standard dose of 0.625 mg CEE. Although long-term RCT outcome data to support the use of low-dose HT are lacking, lower doses may have a more favorable risk to benefit ratio than standard doses while still improving vasomotor symptoms (Bachmann, Schaefers, Uddin, & Utian, 2007; NAMS, 2012). In addition to reducing menopause symptoms, lower estrogen doses have also been found to prevent bone loss (Ettinger et al., 2004; Prestwood, Kenny, Kleppinger, & Kulldorff, 2003).
Transdermal HT preparations Transdermal preparations include patches, gels, lotions, and sprays with a range of dosing options. Specific preparations are listed in Table 3. Because the transdermal route of administration eliminates hepatic first-pass metabolism, much lower doses of HT will successfully alleviate symptoms. Transdermal administration also provides a more consistent level of hormones than oral HT administration (Bachmann et al., 2007; Ettinger et al., 2004; Minkin, 2010). For women with a uterus, addition of a progestin is recommended as it is with oral administration. Combination patches contain-
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ing estradiol (0.05 mg/day) with norethindrone acetate (0.14 or 0.25 mg/day) are available and are comparable to other combined regimens that relieve hot flashes and prevent endometrial hyperplasia (Minkin, 2004, 2010). Researchers have demonstrated that transdermal HT may be associated with a lower risk of venous thrombosis and stroke and may have a more favorable effect on serum triglyceride levels than a comparable dose of oral estrogen (Goodman, 2012; Laliberte et al., 2011). In addition to transdermal patches, other topical preparations include emulsions, gels, and sprays. All preparations are effective for the treatment of vasomotor symptoms. Application instructions for each product vary according to strength and delivery system. The topical estrogen spray preparation has been associated with adverse effects in children and pets that have been exposed to the drug via skin contact (U.S. Food and Drug Administration, 2010). In eight cases of children age 3 to 5, adverse effects included nipple swelling and breast development in girls and breast enlargement in boys. Nurses who work with women using spray preparations need to address safety instructions.
Vaginal creams, tablets, and rings Vaginal estrogen is most commonly used in very low doses for the management of vaginal atrophy. Vaginal administration of estrogen is ideal
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Hormone therapy should be considered only to treat menopause symptoms (primarily vasomotor symptoms) that are negatively affecting a woman’s quality of life.
for treatment of atrophic vaginitis, urinary symptoms, and dyspareunia. Small doses contained in these preparations induce estrogenization of vaginal tissue and have minimal systemic effects. Vaginal estrogen therapy should be considered the primary choice when women complain of localized menopause symptoms such as vaginal dryness, stress incontinence, and frequent urinary tract infections (Smith & Wein, 2010). Clinicians should advise patients to not have intercourse immedi-
ately following vaginal estrogen cream or tablet administration to reduce the risk of penile absorption of estrogen. Although primarily used to treat local symptoms of estrogen deficiency, high doses of vaginal estrogen can be used to treat vasomotor symptoms (Speroff, 2003). The estradiol acetate vaginal ring, which is available in two doses, 0.05 or 0.1 mg of estradiol per day, is approved for the treatment of systemic vasomotor symptoms. Addition of progesterone in women with an intact uterus who are using low-dose vaginal preparations is generally not necessary as there is minimal systemic absorption (NAMS, 2012). However, endometrial hyperplasia should be considered with any new onset of vaginal bleeding in women using these products.
Table 2: Combination Estrogen/Progesterone Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage/day
Premphase
0.625 mg E + 5.0 mg P
Oral continuous-cyclic regimen Conjugated estrogens (E) +
(2 tablets: E and E + P)
medroxyprogesterone acetate (P)
(E alone for days 1–14, followed by E + P on days 15–28) Oral continuous-combined regimen Conjugated estrogens (E) +
Prempro
0.3 or 0.45 mg E + 1.5 mg P (1 tablet)
Femhrt
2.5 μg E + 0.5 mg P (1 tablet);
0.625 mg E + 2.5 or 5.0 mg P (1 tablet);
medroxyprogesterone acetate (P) Ethinyl estradiol (E) +
5 μg E + 1mg P (1 tablet)
norethindrone acetate (P) 17β-estradiol (E) +
Activella
1 mg E + 0.5 mg P (1 tablet)
norethindrone acetate (P) 17β-estradiol (E) +
0.5 mg E + 0.1 mg P (1 tablet);
Angeliq
1 mg E + 0.5 mg P (1 tablet)∗ ; 1 mg E + 1 mg P (1 tablet)∗∗
drospirenone (P) Oral intermittent-combined regimen 17β-estradiol (E) +
Prefest
1 mg E + 0.09 mg P (2 tablets: E and E + P)
norgestimate (P)
(E alone for 3 d, followed by E+P for 3 d, repeated continuously) Transdermal continuous-combined regimen 17β-estradiol (E) + norethindrone acetate (P)
CombiPatch
0.05 mg E + 0.14 mg P (9 cm2 patch, twice/wk); 0.05 mg E + 0.25 mg P (16 cm2 patch, twice/wk)
17β-estradiol (E) + levonorgestrel (P)
Climara Pro
0.045 mg E + 0.015 mg P (22 cm2 patch, once/wk)
Note. E = estrogen; P = progesterone. Adapted with permission from the North American Menopause Society (NAMS).
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Table 3: Transdermal Estrogen Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition 17β-estradiol matrix patch
17β-estradiol reservoir patch 17β-estradiol transdermal gel
Product Name
Dosage
Alora
0.025, 0.05, 0.075, 0.1 twice weekly
Climara
0.025, 0.0375, 0.05, 0.075, 0.1 once/week
Esclim
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Fempatch
0.025 once/week
Menostar
0.014 once/week
Vivelle
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Vivelle-Dot
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Various generics
0.1, 0.05 once or twice/week
Estraderm
0.05, 0.1 twice/week
EstroGel
0.035/day
Elestrin
0.0125/day
Divigel
0.003, 0.009, 0.027/day
17β-estradiol topical emulsion
Estrasorb
0.05/d (2 packets)
17β-estradiol transdermal spray
Evamist
0.021/90 μL/d (increase to 1.5/90 μL/day if needed)
Note. Adapted with permission from the North American Menopause Society (NAMS).
Progestin preparations Endometrial hyperplasia and cancer can occur with unopposed estrogen therapy, therefore progestin should be added to estrogen therapy in women who have intact uteruses. Medroxyprogesterone acetate (MPA) is the most commonly prescribed progestin and is typically given in an oral cyclic regimen or continuous regimen. Natural oral micronized progesterone is also an option that has minimal impact on lipids (Cheung, 2000) and may be associated with less vaginal bleeding than MPA (Linderfield & Langer, 2002). Micronized progesterone has not been studied as thoroughly as MPA, but it may be an option if women are having side effects attributable to MPA.
Contraindications Most women age 50 to 59 with moderate to severe vasomotor symptoms are candidates for shortterm HT for symptomatic relief. Exceptions include women with known coronary artery disease, a previous venous thromboembolic event or stroke, active liver disease, or those at high risk for these complications. Women with a known (i.e., current) or suspected breast, ovarian, or uterine neoplasia or women with undiagnosed, abnormal vaginal bleeding should not take HT. Pregnancy should be ruled out prior to beginning HT (NAMS, 2010; Santen et al., 2010; Shifren & Schiff, 2010).
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Complementary/Alternative Therapies Although well-established efficacy data are limited and conflicting, the use of non-FDA-approved complementary and alternative therapies to reduce menopause symptoms has gained popularity among women who desire symptom relief but are not interested in using prescription HT (Tong, 2013). It is estimated that more than 50% of menopausal and postmenopausal women will try nonprescription products such as herbal preparations and vitamins to help manage vasomotor symptoms (Keenan et al., 2003). However, products are often not standardized or regulated, and therefore the amount of active ingredient can vary widely between manufacturers. Of all complementary and alternative therapies, phytoestrogens (soy), and black cohosh have been most widely studied (Tong, 2013). Phytoestrogens (primarily isoflavones) are naturally occurring plant-based substances that bind to estrogen receptors and contain estrogenic and antiestrogenic properties (Krebs, Ensrud, MacDonald, & Wilt, 2004). Isoflavones are present in soy-based foods and red clover extracts. Researchers investigating whether ingestion of these items resulted in a reduction of vasomotor symptoms related to menopause reported mixed
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Table 4: Vaginal Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage
Estrace Vaginal Cream
Initial: 2–4 g/day for 1–2 week
Vaginal creams 17β-estradiol
Maintenance: 1 g/day (0.1 mg active ingredient/g) Conjugated estrogens
Premarin Vaginal Cream
For vaginal atrophy: 0.5–2 g/day for 21 day then off 7 day For dyspareunia: 0.5 g/day for 21 day then off 7 day, or twice/week (0.625 mg active ingredient/g)
Vaginal rings 17β-estradiol
Estring
Device containing 2 mg releases 7.5 μg/day for 90 days (for vulvovaginal Atrophy
Estradiol acetate
Femring
Device containing 12.4 mg or 24.8 mg estradiol acetate releases 0.05 mg/day or 0.10 mg/day estradiol for 90 days (both doses release systemic levels for treatment of vulvovaginal atrophy and vasomotor symptoms)
Vaginal tablet Estradiol hemihydrate
Vagifem
Initial: 1 tablet/d for 2 week Maintenance: 1 tablet twice/week (tablet containing 25.8 μg or 10 μg of estradiol hemihydrates, equivalent to 10 μg or 25 μg of estradiol; for
Note. Adapted with permission from the North American Menopause Society (NAMS).
results. Researchers conducting systematic reviews and randomized controlled trials have concluded that soy-based products have demonstrated no improvement in vasomotor symptoms related to menopause compared to placebo (Krebs et al., 2004; Newton et al., 2006). In other studies, researchers suggested phytoestrogen supplements reduced the frequency and severity of vasomotor symptoms when compared to placebo, but these studies were reported to be underpowered and lacking methodological rigor (Lethaby et al., 2007).
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erties. Evidence supporting the effectiveness of black cohosh is conflicting due to differences in study design and lack of standardization among doses (Tong, 2013). Researchers have reported that compared with placebo, black cohosh did not reduce vasomotor or vaginal symptoms (Newton et al., 2006; Reed et al., 2008).
Clinical Implications
Black cohosh is an herb that is sold as a dietary supplement in the United States. The mechanism of action on menopause symptoms is unclear, although it may have estrogenic prop-
Nurses who work with women experiencing menopause are in position to provide education and clarity regarding treatment options for menopause symptoms. Women may be fearful of potential side effects or adverse outcomes of HT. They may also have difficulty interpreting HT study
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results that present broad findings and applying the information to their own specific situations. Therefore, individualized information is the cornerstone for education and counseling. Women need to receive information that is tailored to their specific needs and concerns. The risks and benefits of HT are not static and change as women age and transition through menopause. In addition to baseline education, risks and benefits of HT need to be assessed and reviewed with women at each visit based on their ages, current symptoms, concerns, comorbid conditions, and lifestyles. Nurses can assist women in identifying their most bothersome symptoms and offer guidance on available treatment options, including prescription HT and complementary and alternative therapies. If HT is initiated, women should be counseled on potential side effects and strategies to minimize these effects. Common side effects include breast tenderness, headaches, mood changes, and fluid retention (NAMS, 2010). Women should be encouraged to report any new symptoms they believe are associated with HT. Many side effects can be minimized and/or improved with either a reduction in HT dose or change in route of administration. Women should be reminded that because everyone experiences different responses to medication, it may take more than one medication adjustment to decrease or eliminate side effects. Additionally, when HT is started at doses lower than traditionally prescribed (<0.625 mg CEE), it should be expected that women may ex-
Individualized information is the cornerstone for education and counseling on menopause.
perience longer treatment periods prior to relief of vasomotor symptoms (NAMS, 2012). Even though no rigorous evidence supports the effectiveness of nonprescription supplements such as soy and black cohosh, women may still be interested in trying these products. It is possible that women may experience relief through a placebo effect, and side effects are generally mild and include gastrointestinal complaints such as bloating and nausea (Lethaby et al., 2009). Nurses should provide clear, evidence-based information about the effectiveness of supplements and remind women to inform their health care providers of any medications they take, including over-thecounter products. Nurses can provide anticipatory guidance to women experiencing menopause and offer suggestions for evidence-based resources, including information on lifestyle changes that can decrease vasomotor symptoms associated with menopause (Table 5). Additionally, health promotion information can be offered during educational sessions. Cardiovascular disease is the leading cause of death among women (Kochanek, Xu, Murphy, Minino, ˜ & Kung, 2011), and as women experience menopause they should be reminded that health issues are not inevitable with aging, and many
Table 5: Adjunct Strategies for Managing Discomforts of Menopause Identify and avoid vasomotor triggers
Hot/warm temperatures, alcohol, spicy foods, hot beverages
Clothing
Dress in layers; remove layers as needed during hot flushes
Exercise
Exercise regularly to regulate body temperature
Smoking
Smoking is associated with exacerbating hot flushes Women should quit smoking for overall health
Environmental temperature
Keep air temperature of home and work space cool
Urinary and vaginal symptoms
Pelvic floor exercises Over the counter vaginal lubricants
Relaxation Health promotion
Relaxation techniques such as deep breathing may help alleviate hot flashes Stress reduction, regular health maintenance visits, routine screening for disease as appropriate (Pap smear, mammography, colonoscopy, lipid profile, diabetes)
Complementary therapies
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Yoga, acupuncture, acupressure, guided imagery
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can be prevented. A healthy diet, regular exercise, smoking cessation, and weight loss are all protective for the development of cardiovascular disease and should be incorporated into education about menopause.
ultralow-dose transdermal estradiol on bone mineral density: A randomized clinical trial. Obstetrics &Gynecology, 104(3), 443–451. Food and Drug Administration. (2010). Consumer health information/U.S. Food and Drug Administration, July 2010. Retrieved from
http://www.fda.gov/ForConsumers/ConsumerUpdates/
ucm220217.htm Goodman, M. P. (2012). Are all estrogens created equal? A review of
Conclusions
oral vs. transdermal therapy. Journal of Women’s Health, 21(2),
Menopause is a universal event for women. Some women may progress through menopause without incident, whereas others may experience symptoms that produce concern and result in health care visits. Menopause is also a time when women can focus on their health and lifestyles and make changes that will decrease the chances of developing chronic illnesses. During this time, nurses have the opportunity to provide anticipatory guidance, education, and clarity about the normal process of menopause and available treatment options. Through individualized education and counseling, women will receive comprehensive information that will allow them to make the best choices for their own health promotion.
161–169. doi:10.1089/jwh.2011.2839 Gorodeski, G. I. (2012). Effects of estrogen on vaginal innervation: Denervation or remodeling? Menopause: The Journal of the North American Menopause Society, 19(6), 604–605. doi:10.1097.gme.0b013e31824f5cbb Harlow, S. D., Gass, M., Hall, J. E., Lobo, R., Maki, P., Rebar, R. W., . . . de Villiers, T. J. (2012). Executive summary of the Stages of Reproductive Aging Workshop +10: Addressing the unfinished agenda of staging reproductive aging. Climacteric, 15(2), 105– 114. doi:10.3109/13697137.2011.650656 Harman, S. M., Vittinghoff, E., Brinton, E. A., Budoff, M. J., Cedars, M. I., Lobo, R. A., . . . Black, D. M. (2011). Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. American Journal of Medicine, 124(3), 199–205. doi:10.1026/j.amjmed.2010.09.021 Hersh, A. L., Stefanick, M. L., & Stafford, R. S. (2004). National use of post-menopausal hormone therapy: Annual trends and response to recent evidence. Journal of the American Medical Association, 291, 47–53. doi:10.1089/jwh.2012.3602
Acknowledgement
Hess, R, Thurston, R. C., Hays, R. D., Chang, C.-C. H., Dillon, S.
The authors thank Julianne A. Hazard, RN, BS for her assistance with focused literatures searches.
N., Ness, R. B., . . . Matthews, K. A. (2012). The impact of menopause on health-related quality of life: Results from the STRIDE longitudinal study. Quality of Life Research, 21, 535– 544. doi:10.1007/s11136-011-9959-7 Keenan,
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Hormone Therapy for the Management of Menopause Symptoms Heidi Collins Fantasia and Melissa A. Sutherland
ABSTRACT Many women will undergo menopause without incident, but others will experience bothersome effects resulting from declining estrogen levels. Vasomotor symptoms, which manifest as intense feelings of warmth, flushing, and perspiration, are the most common symptoms for which women seek treatment. Hormone therapy is indicated for the relief of vasomotor symptoms related to menopause. We review current Food Drug Administration-approved options for hormone therapy and discuss implications for practice and patient education.
JOGNN, 43, 226-235; 2014. DOI: 10.1111/1552-6909.12282 Accepted May 2013
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Keywords menopause hormone therapy vasomotor symptoms estrogen progesterone
Correspondence Heidi Collins Fantasia, PhD, RN, WHNP-BC, University of Massachusetts Lowell, College of Health Sciences, School of Nursing, 113 Wilder Street, Lowell, MA 01854. [email protected]
The authors and planners for this activity report no conflict of interest or relevant financial relationships. The article includes no discussion of off-label drug or device use. No commercial support was received for this educational activity. Heidi Collins Fantasia, PhD, RN, WHNP-BC, is an assistant professor in the College of Health Sciences, School of Nursing at the University of Massachusetts Lowell and a nurse practitioner for Health Quarters, Beverly, MA.
ccording to the U.S. Census Bureau demographic profile, in 2010 there were almost 23 million women in the United States between the ages of 45 and 54 (U.S. Census Bureau, 2010), and the average age of natural menopause in the United States is 51 (North American Menopause Society [NAMS], 2013). This physiologic transition is a universal event that affects all women and marks the end of reproductive capability. It is influenced by a myriad of factors, including genetics, environment, diet, weight, smoking, and overall health status (NAMS, 2010).
A
Vasomotor instability that occurs as a result of declining estrogen levels can have a negative impact on the quality of life and is often the main symptom of menopause that causes women to seek treatment (Avis et al., 2009; Burleson, Todd, & Trevathan, 2010; Hess et al., 2012). Hormone therapy is approved by the Food and Drug Administration (FDA) as the most effective treatment for vasomotor symptoms of menopause (NAMS, 2012) but is currently underused due to concerns regarding potential side effects, including risk for breast cancer and venous thromboembolism (Hersh, Stefanick, & Stafford, 2004; Neal-Perry & Pal, 2011; Newton et al., 2010). Patients and health care providers may overestimate the potential for harm and underestimate the potential benefits of hormone therapy (HT) (Rees, 2005). In this article we review current FDA-approved hormonal pharmacologic options for women experiencing symptoms of menopause, discuss the controversy
surrounding HT, and discuss clinical implications for nurses who work with women experiencing the transition through menopause.
Diagnosis of Menopause Menopause can only be diagnosed retrospectively, and menstrual cycle details provided by women represent the most important information to determine menopause status (Harlow et al., 2012). Menopause is defined as occurring after 12 months of amenorrhea that results from the loss of ovarian follicular activity that cannot be attributed to another physiologic or pathologic cause (NAMS, 2010; National Institutes of Health [NIH], 2005; World Health Organization [WHO], 1996). The years preceding the permanent cessation of menses are characterized by endocrine changes that affect menstrual cycle frequency, amount, and duration (NAMS, 2010). Although physiologic signs of hormone fluctuation during menopause may occur, no one specific laboratory or diagnostic test to determine if a patient is menopausal exists. Hormonal biomarker assays, especially for follicle stimulating hormone (FSH), are not reliable due to lack of international standardization and wide variability among women (Harlow et al., 2012; NAMS, 2010). Elevated FSH levels > 30 IU/ml are indicative of increasing ovarian follicular atresia, but laboratory measurements cannot confirm menopause (Harlow et al., 2012; O’Neill & Eden, 2012).
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Symptoms of Menopause Vasomotor Instability Vasomotor instability (or hot flashes), a primary symptom of menopause, includes a sudden feeling of intense heat accompanied by perspiration and flushing (NIH, 2005) and typically lasts less than 10 minutes. Vasomotor instability may also be associated with symptoms of anxiety, palpitations, and sleep disturbances. Although the prevalence of vasomotor symptoms varies across racial and ethnic backgrounds, more than 50% of women report vasomotor symptoms at some point during menopause (O’Neill & Eden, 2012).
Hypoestrogenic Changes Declining estrogen levels are associated with urogenital atrophy. Vulvar and vaginal symptoms may include dryness, pruritus, burning, and pain, especially with intercourse (Gorodeski, 2012). Although the natural aging process is a contributing factor to urogenital symptoms, estrogen deficiency has been established as the main etiology of vaginal epithelial thinning and atrophic vaginitis (Gorodeski, 2012; O’Neill & Eden, 2012).
The Women’s Health Initiative Hormone Trials The Women’s Health Initiative (WHI) clinical trials were parallel, multicenter, randomized, controlled primary prevention trials designed to investigate the effects of hormone therapy (HT) on major health issues in postmenopausal women such as coronary artery disease (CAD). The primary adverse outcome of the research trials was invasive breast cancer (Rossouw et al., 2002; Anderson et al., 2004). Researchers studied multiple foci and in one arm compared daily estrogen (conjugated equine estrogen [CEE] 0.625 mg) plus progesterone (medroxyprogesterone acetate [MPA] 2.5mg) with a placebo for the primary prevention of cardiovascular disease among postmenopausal women. A total of 16,608 healthy, postmenopausal women with an intact uterus and a baseline age of 50 to 79 were enrolled between 1993 and 1998. In May of 2002 after 5 out of 8 years of anticipated follow-up, the estrogen plus progesterone arm was halted by the study’s Data Safety Monitoring Board after unanticipated risks were judged to outweigh potential benefits. Compared to women receiving placebo, women in the estrogen/progesterone group had increased risks of breast cancer, stroke, pulmonary embolism, and myocardial infarction (Rossouw et al., 2002).
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The early termination of the estrogen plus progesterone and estrogen only arms of the Women’s Health Initiative has shaped the pharmacologic treatment of menopause symptoms.
The estrogen-only arm of the study was also terminated early. In this portion of the WHI, 10,739 postmenopausal women age 50 to 70 who had undergone a hysterectomy were enrolled. These women received daily estrogen (0.625 mg CEE) without added progesterone. Early termination occurred when investigators reported that when compared with placebo, the use of daily estrogen increased the risk of stroke and did not reduce the incidence of CAD (Anderson et al., 2004).
Rethinking WHI Study Results The early termination of both arms of the WHI has shaped the subsequent pharmacologic treatment of menopause symptoms. Prior to the publication of the WHI results, HT was most commonly prescribed to control the vasomotor symptoms of menopause that are experienced by more than one half of perimenopausal and postmenopausal women (Santen et al., 2010). When the initial research results were published, use of HT declined significantly as a result of patient and provider concerns and fear of potential liability if adverse events were to occur (Hersh et al., 2004; Neal-Perry & Pal, 2011; Newton et al., 2010). Since the initial publication of the WHI results, the original research conclusions regarding risks of adverse events have been questioned and limitations closely examined (Utian, 2012). Three limitations often cited include the age of the sample, the determination of relative risk, and the formulation of the HT. The age range for inclusion in the WHI trials was 50 to 79, and the mean age was 63 (Rossouw et al., 2002). The age range of almost 20 years was necessary due to the large numbers of participants needed to adequately power the study and achieve statistical significance for the small number of predicted adverse outcomes (Anderson et al., 2004; Rossouw et al., 2002). However, the average age of participants (63) was more than 10 years older than the age at which women would typically be offered HT for symptoms of menopause. As women age their risks for cardiovascular incidents such as myocardial infarction and thromboembolic events increase. Therefore, it is challenging to determine whether the adverse cardiovascular events that
Melissa A. Sutherland, PhD, FNP-BC, is an assistant professor at the William F. Connell School of Nursing, Boston College, Chestnut Hill, MA and a certified family nurse practitioner.
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occurred among participants in the WHI trials were associated with the addition of HT, the natural aging process, or both (Utian, 2012). Another critique is that the researchers overstated their conclusions related to the risk of adverse events. The results were interpreted in terms of relative risk, that is, the risk of an adverse event as a result of receiving the HT intervention compared to not receiving the intervention. Researchers who have reviewed the conclusions of the WHI study have questioned whether outcomes should have instead been interpreted in terms of absolute risk, that is, the individual participant’s baseline risk of having an adverse event prior to the intervention and reporting the risk post-intervention (Clark, 2006; Utian, 2012). The last critique relates to the HT formulations that were used. The WHI researchers only evaluated the use of oral HT preparations based on one formulation and dose of estrogen (0.625 mg CEE) and progesterone (2.5mg MPA). The researchers acknowledged this limitation and the fact that the results may not apply to HT delivered by another route, dose, or different hormonal compound (Anderson et al., 2004; Rossouw et al., 2002).
Current Hormone Therapy Recommendations Prior to the publication of the WHI results, HT was routinely prescribed not only for the control of vasomotor symptoms, but also for the prevention of chronic health conditions (Nelson, Walker, Zakher, & Mitchell, 2012). Currently, HT should be considered only to treat menopausal symptoms (primarily vasomotor symptoms) that negatively affect quality of life (NAMS, 2012). It should not be prescribed to prevent chronic conditions such as cardiovascular disease, dementia, osteoporosis, and colorectal cancer. Additionally, evidence suggests that the timing of HT initiation may be important to consider when counseling women who are considering HT for symptoms of menopause (Harman et al., 2011). In women who have been menopausal for less than ten years (typically in the age range of 50–59), short-term use of HT has not been associated with an increase in mortality or heart disease (Harman et al., 2011; Rossouw et al., 2007; Stram et al., 2011). Currently, shortterm use is defined as 5 years (Rossouw, Manson, Kaunitz, & Anderson, 2013).
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FDA-Approved Pharmacologic Options The NAMS supports the use of FDA-approved HT as the most effective treatment of moderate to severe menopause related vasomotor symptoms in women without contraindications to estrogen or estrogen/progesterone (NAMS, 2012). Because no randomized controlled trials (RCTs) have been conducted to compare hormone dosage and/or route of administration, the NAMS recommends that the lowest dose of FDA approved estrogen or estrogen plus progesterone that is effective for treating and controlling symptoms should be used for the shortest amount of time (NAMS, 2012). Route of delivery (oral, transdermal, vaginal) should be determined after an individualized discussion with each woman and reflect her lifestyle and preferences. Individual oral, transdermal, and vaginal preparations are listed in Tables 1 through 4.
Oral HT preparations Oral HT is available as either estrogen-only or estrogen-plus-progesterone preparations. Systemic oral estrogen is most often prescribed to manage vasomotor symptoms. Individual preparations and doses are listed in Tables 1 and 2. Several important factors should be considered prior to prescribing oral HT. For women with a uterus, addition of a progestin is recommended to reduce the risk of endometrial hyperplasia from exposure to unopposed estrogen. Additional progesterone can be added in either a cyclic or continuous fashion. Progesterone that is taken on a continuous, daily basis with estrogen will avoid a monthly withdrawal bleed that occurs when progesterone is taken cyclically in either the first or second one half of the month. Oral administration of estrogen has a greater effect on the liver due to the first-pass effect. To overcome the effects of hepatic metabolism, oral HT must be given in higher doses than transdermal HT to achieve a serum concentration that is great enough to relieve vasomotor symptoms (Kopper, Gudeman, & Thompson, 2008). Oral estrogen products increase C-reactive protein (CRP) that is associated with inflammation and tissue damage and may lead to atherosclerotic cardiovascular disease, especially with long-term use of more than 5 years (Goodman, 2012). Oral estrogen has a favorable effect on lipid profiles through an increase in high-density lipoprotein (HDL) and a decrease in low-density lipoprotein (LDL) but
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Table 1: Oral Estrogen Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage (mg/day)
Conjugated estrogens
Premarin
0.3, 0.45,∗ 0.625, 0.9, 1.25
Synthetic conjugated estrogens, A
Cenestin
0.3. 0.45, 0.625, 0.9, 1.25
Synthetic conjugated estrogens, B
Enjuvia
0.3, 0.45, 0.625, 0.9, 1.25
Esterified estrogens
Menest
0.3, 0.625, 1.25, 2.5
17β-estradiol
Estrace,
0.5, 1.0, 2.0
Various generics
0.5, 1.0, 2.0
Estradiol acetate
Femtrace
0.45, 0.9, 1.8
Estropipate
Ortho-Est
0.625 (0.75 estropipate), 1.25 (1.5), 2.5 (3.0), 5.0 (6.0)
Ogen
0.625 (0.75 estropipate), 1.25 (1.5), 2.5 (3.0)
Various generics
0.625 (0.75), 1.5 (3.0), 5.0 (6.0)
Note. Adapted with permission from the North American Menopause Society (NAMS).
increases triglyceride levels, which is an independent risk factor for stroke (Goodman, 2012). Oral estrogen preparations are available in a wide range of doses, and HT can be tailored based upon the severity of vasomotor symptoms. The health risks of HT discovered in the WHI trials were associated with a standard dose of 0.625 mg CEE. Although long-term RCT outcome data to support the use of low-dose HT are lacking, lower doses may have a more favorable risk to benefit ratio than standard doses while still improving vasomotor symptoms (Bachmann, Schaefers, Uddin, & Utian, 2007; NAMS, 2012). In addition to reducing menopause symptoms, lower estrogen doses have also been found to prevent bone loss (Ettinger et al., 2004; Prestwood, Kenny, Kleppinger, & Kulldorff, 2003).
Transdermal HT preparations Transdermal preparations include patches, gels, lotions, and sprays with a range of dosing options. Specific preparations are listed in Table 3. Because the transdermal route of administration eliminates hepatic first-pass metabolism, much lower doses of HT will successfully alleviate symptoms. Transdermal administration also provides a more consistent level of hormones than oral HT administration (Bachmann et al., 2007; Ettinger et al., 2004; Minkin, 2010). For women with a uterus, addition of a progestin is recommended as it is with oral administration. Combination patches contain-
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ing estradiol (0.05 mg/day) with norethindrone acetate (0.14 or 0.25 mg/day) are available and are comparable to other combined regimens that relieve hot flashes and prevent endometrial hyperplasia (Minkin, 2004, 2010). Researchers have demonstrated that transdermal HT may be associated with a lower risk of venous thrombosis and stroke and may have a more favorable effect on serum triglyceride levels than a comparable dose of oral estrogen (Goodman, 2012; Laliberte et al., 2011). In addition to transdermal patches, other topical preparations include emulsions, gels, and sprays. All preparations are effective for the treatment of vasomotor symptoms. Application instructions for each product vary according to strength and delivery system. The topical estrogen spray preparation has been associated with adverse effects in children and pets that have been exposed to the drug via skin contact (U.S. Food and Drug Administration, 2010). In eight cases of children age 3 to 5, adverse effects included nipple swelling and breast development in girls and breast enlargement in boys. Nurses who work with women using spray preparations need to address safety instructions.
Vaginal creams, tablets, and rings Vaginal estrogen is most commonly used in very low doses for the management of vaginal atrophy. Vaginal administration of estrogen is ideal
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Hormone therapy should be considered only to treat menopause symptoms (primarily vasomotor symptoms) that are negatively affecting a woman’s quality of life.
for treatment of atrophic vaginitis, urinary symptoms, and dyspareunia. Small doses contained in these preparations induce estrogenization of vaginal tissue and have minimal systemic effects. Vaginal estrogen therapy should be considered the primary choice when women complain of localized menopause symptoms such as vaginal dryness, stress incontinence, and frequent urinary tract infections (Smith & Wein, 2010). Clinicians should advise patients to not have intercourse immedi-
ately following vaginal estrogen cream or tablet administration to reduce the risk of penile absorption of estrogen. Although primarily used to treat local symptoms of estrogen deficiency, high doses of vaginal estrogen can be used to treat vasomotor symptoms (Speroff, 2003). The estradiol acetate vaginal ring, which is available in two doses, 0.05 or 0.1 mg of estradiol per day, is approved for the treatment of systemic vasomotor symptoms. Addition of progesterone in women with an intact uterus who are using low-dose vaginal preparations is generally not necessary as there is minimal systemic absorption (NAMS, 2012). However, endometrial hyperplasia should be considered with any new onset of vaginal bleeding in women using these products.
Table 2: Combination Estrogen/Progesterone Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage/day
Premphase
0.625 mg E + 5.0 mg P
Oral continuous-cyclic regimen Conjugated estrogens (E) +
(2 tablets: E and E + P)
medroxyprogesterone acetate (P)
(E alone for days 1–14, followed by E + P on days 15–28) Oral continuous-combined regimen Conjugated estrogens (E) +
Prempro
0.3 or 0.45 mg E + 1.5 mg P (1 tablet)
Femhrt
2.5 μg E + 0.5 mg P (1 tablet);
0.625 mg E + 2.5 or 5.0 mg P (1 tablet);
medroxyprogesterone acetate (P) Ethinyl estradiol (E) +
5 μg E + 1mg P (1 tablet)
norethindrone acetate (P) 17β-estradiol (E) +
Activella
1 mg E + 0.5 mg P (1 tablet)
norethindrone acetate (P) 17β-estradiol (E) +
0.5 mg E + 0.1 mg P (1 tablet);
Angeliq
1 mg E + 0.5 mg P (1 tablet)∗ ; 1 mg E + 1 mg P (1 tablet)∗∗
drospirenone (P) Oral intermittent-combined regimen 17β-estradiol (E) +
Prefest
1 mg E + 0.09 mg P (2 tablets: E and E + P)
norgestimate (P)
(E alone for 3 d, followed by E+P for 3 d, repeated continuously) Transdermal continuous-combined regimen 17β-estradiol (E) + norethindrone acetate (P)
CombiPatch
0.05 mg E + 0.14 mg P (9 cm2 patch, twice/wk); 0.05 mg E + 0.25 mg P (16 cm2 patch, twice/wk)
17β-estradiol (E) + levonorgestrel (P)
Climara Pro
0.045 mg E + 0.015 mg P (22 cm2 patch, once/wk)
Note. E = estrogen; P = progesterone. Adapted with permission from the North American Menopause Society (NAMS).
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Table 3: Transdermal Estrogen Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition 17β-estradiol matrix patch
17β-estradiol reservoir patch 17β-estradiol transdermal gel
Product Name
Dosage
Alora
0.025, 0.05, 0.075, 0.1 twice weekly
Climara
0.025, 0.0375, 0.05, 0.075, 0.1 once/week
Esclim
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Fempatch
0.025 once/week
Menostar
0.014 once/week
Vivelle
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Vivelle-Dot
0.025, 0.0375, 0.05, 0.075, 0.1 twice/week
Various generics
0.1, 0.05 once or twice/week
Estraderm
0.05, 0.1 twice/week
EstroGel
0.035/day
Elestrin
0.0125/day
Divigel
0.003, 0.009, 0.027/day
17β-estradiol topical emulsion
Estrasorb
0.05/d (2 packets)
17β-estradiol transdermal spray
Evamist
0.021/90 μL/d (increase to 1.5/90 μL/day if needed)
Note. Adapted with permission from the North American Menopause Society (NAMS).
Progestin preparations Endometrial hyperplasia and cancer can occur with unopposed estrogen therapy, therefore progestin should be added to estrogen therapy in women who have intact uteruses. Medroxyprogesterone acetate (MPA) is the most commonly prescribed progestin and is typically given in an oral cyclic regimen or continuous regimen. Natural oral micronized progesterone is also an option that has minimal impact on lipids (Cheung, 2000) and may be associated with less vaginal bleeding than MPA (Linderfield & Langer, 2002). Micronized progesterone has not been studied as thoroughly as MPA, but it may be an option if women are having side effects attributable to MPA.
Contraindications Most women age 50 to 59 with moderate to severe vasomotor symptoms are candidates for shortterm HT for symptomatic relief. Exceptions include women with known coronary artery disease, a previous venous thromboembolic event or stroke, active liver disease, or those at high risk for these complications. Women with a known (i.e., current) or suspected breast, ovarian, or uterine neoplasia or women with undiagnosed, abnormal vaginal bleeding should not take HT. Pregnancy should be ruled out prior to beginning HT (NAMS, 2010; Santen et al., 2010; Shifren & Schiff, 2010).
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Complementary/Alternative Therapies Although well-established efficacy data are limited and conflicting, the use of non-FDA-approved complementary and alternative therapies to reduce menopause symptoms has gained popularity among women who desire symptom relief but are not interested in using prescription HT (Tong, 2013). It is estimated that more than 50% of menopausal and postmenopausal women will try nonprescription products such as herbal preparations and vitamins to help manage vasomotor symptoms (Keenan et al., 2003). However, products are often not standardized or regulated, and therefore the amount of active ingredient can vary widely between manufacturers. Of all complementary and alternative therapies, phytoestrogens (soy), and black cohosh have been most widely studied (Tong, 2013). Phytoestrogens (primarily isoflavones) are naturally occurring plant-based substances that bind to estrogen receptors and contain estrogenic and antiestrogenic properties (Krebs, Ensrud, MacDonald, & Wilt, 2004). Isoflavones are present in soy-based foods and red clover extracts. Researchers investigating whether ingestion of these items resulted in a reduction of vasomotor symptoms related to menopause reported mixed
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Table 4: Vaginal Products Approved for Postmenopause Use in the United States by the Food and Drug Administration Composition
Product Name
Dosage
Estrace Vaginal Cream
Initial: 2–4 g/day for 1–2 week
Vaginal creams 17β-estradiol
Maintenance: 1 g/day (0.1 mg active ingredient/g) Conjugated estrogens
Premarin Vaginal Cream
For vaginal atrophy: 0.5–2 g/day for 21 day then off 7 day For dyspareunia: 0.5 g/day for 21 day then off 7 day, or twice/week (0.625 mg active ingredient/g)
Vaginal rings 17β-estradiol
Estring
Device containing 2 mg releases 7.5 μg/day for 90 days (for vulvovaginal Atrophy
Estradiol acetate
Femring
Device containing 12.4 mg or 24.8 mg estradiol acetate releases 0.05 mg/day or 0.10 mg/day estradiol for 90 days (both doses release systemic levels for treatment of vulvovaginal atrophy and vasomotor symptoms)
Vaginal tablet Estradiol hemihydrate
Vagifem
Initial: 1 tablet/d for 2 week Maintenance: 1 tablet twice/week (tablet containing 25.8 μg or 10 μg of estradiol hemihydrates, equivalent to 10 μg or 25 μg of estradiol; for
Note. Adapted with permission from the North American Menopause Society (NAMS).
results. Researchers conducting systematic reviews and randomized controlled trials have concluded that soy-based products have demonstrated no improvement in vasomotor symptoms related to menopause compared to placebo (Krebs et al., 2004; Newton et al., 2006). In other studies, researchers suggested phytoestrogen supplements reduced the frequency and severity of vasomotor symptoms when compared to placebo, but these studies were reported to be underpowered and lacking methodological rigor (Lethaby et al., 2007).
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erties. Evidence supporting the effectiveness of black cohosh is conflicting due to differences in study design and lack of standardization among doses (Tong, 2013). Researchers have reported that compared with placebo, black cohosh did not reduce vasomotor or vaginal symptoms (Newton et al., 2006; Reed et al., 2008).
Clinical Implications
Black cohosh is an herb that is sold as a dietary supplement in the United States. The mechanism of action on menopause symptoms is unclear, although it may have estrogenic prop-
Nurses who work with women experiencing menopause are in position to provide education and clarity regarding treatment options for menopause symptoms. Women may be fearful of potential side effects or adverse outcomes of HT. They may also have difficulty interpreting HT study
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results that present broad findings and applying the information to their own specific situations. Therefore, individualized information is the cornerstone for education and counseling. Women need to receive information that is tailored to their specific needs and concerns. The risks and benefits of HT are not static and change as women age and transition through menopause. In addition to baseline education, risks and benefits of HT need to be assessed and reviewed with women at each visit based on their ages, current symptoms, concerns, comorbid conditions, and lifestyles. Nurses can assist women in identifying their most bothersome symptoms and offer guidance on available treatment options, including prescription HT and complementary and alternative therapies. If HT is initiated, women should be counseled on potential side effects and strategies to minimize these effects. Common side effects include breast tenderness, headaches, mood changes, and fluid retention (NAMS, 2010). Women should be encouraged to report any new symptoms they believe are associated with HT. Many side effects can be minimized and/or improved with either a reduction in HT dose or change in route of administration. Women should be reminded that because everyone experiences different responses to medication, it may take more than one medication adjustment to decrease or eliminate side effects. Additionally, when HT is started at doses lower than traditionally prescribed (<0.625 mg CEE), it should be expected that women may ex-
Individualized information is the cornerstone for education and counseling on menopause.
perience longer treatment periods prior to relief of vasomotor symptoms (NAMS, 2012). Even though no rigorous evidence supports the effectiveness of nonprescription supplements such as soy and black cohosh, women may still be interested in trying these products. It is possible that women may experience relief through a placebo effect, and side effects are generally mild and include gastrointestinal complaints such as bloating and nausea (Lethaby et al., 2009). Nurses should provide clear, evidence-based information about the effectiveness of supplements and remind women to inform their health care providers of any medications they take, including over-thecounter products. Nurses can provide anticipatory guidance to women experiencing menopause and offer suggestions for evidence-based resources, including information on lifestyle changes that can decrease vasomotor symptoms associated with menopause (Table 5). Additionally, health promotion information can be offered during educational sessions. Cardiovascular disease is the leading cause of death among women (Kochanek, Xu, Murphy, Minino, ˜ & Kung, 2011), and as women experience menopause they should be reminded that health issues are not inevitable with aging, and many
Table 5: Adjunct Strategies for Managing Discomforts of Menopause Identify and avoid vasomotor triggers
Hot/warm temperatures, alcohol, spicy foods, hot beverages
Clothing
Dress in layers; remove layers as needed during hot flushes
Exercise
Exercise regularly to regulate body temperature
Smoking
Smoking is associated with exacerbating hot flushes Women should quit smoking for overall health
Environmental temperature
Keep air temperature of home and work space cool
Urinary and vaginal symptoms
Pelvic floor exercises Over the counter vaginal lubricants
Relaxation Health promotion
Relaxation techniques such as deep breathing may help alleviate hot flashes Stress reduction, regular health maintenance visits, routine screening for disease as appropriate (Pap smear, mammography, colonoscopy, lipid profile, diabetes)
Complementary therapies
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Yoga, acupuncture, acupressure, guided imagery
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can be prevented. A healthy diet, regular exercise, smoking cessation, and weight loss are all protective for the development of cardiovascular disease and should be incorporated into education about menopause.
ultralow-dose transdermal estradiol on bone mineral density: A randomized clinical trial. Obstetrics &Gynecology, 104(3), 443–451. Food and Drug Administration. (2010). Consumer health information/U.S. Food and Drug Administration, July 2010. Retrieved from
http://www.fda.gov/ForConsumers/ConsumerUpdates/
ucm220217.htm Goodman, M. P. (2012). Are all estrogens created equal? A review of
Conclusions
oral vs. transdermal therapy. Journal of Women’s Health, 21(2),
Menopause is a universal event for women. Some women may progress through menopause without incident, whereas others may experience symptoms that produce concern and result in health care visits. Menopause is also a time when women can focus on their health and lifestyles and make changes that will decrease the chances of developing chronic illnesses. During this time, nurses have the opportunity to provide anticipatory guidance, education, and clarity about the normal process of menopause and available treatment options. Through individualized education and counseling, women will receive comprehensive information that will allow them to make the best choices for their own health promotion.
161–169. doi:10.1089/jwh.2011.2839 Gorodeski, G. I. (2012). Effects of estrogen on vaginal innervation: Denervation or remodeling? Menopause: The Journal of the North American Menopause Society, 19(6), 604–605. doi:10.1097.gme.0b013e31824f5cbb Harlow, S. D., Gass, M., Hall, J. E., Lobo, R., Maki, P., Rebar, R. W., . . . de Villiers, T. J. (2012). Executive summary of the Stages of Reproductive Aging Workshop +10: Addressing the unfinished agenda of staging reproductive aging. Climacteric, 15(2), 105– 114. doi:10.3109/13697137.2011.650656 Harman, S. M., Vittinghoff, E., Brinton, E. A., Budoff, M. J., Cedars, M. I., Lobo, R. A., . . . Black, D. M. (2011). Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. American Journal of Medicine, 124(3), 199–205. doi:10.1026/j.amjmed.2010.09.021 Hersh, A. L., Stefanick, M. L., & Stafford, R. S. (2004). National use of post-menopausal hormone therapy: Annual trends and response to recent evidence. Journal of the American Medical Association, 291, 47–53. doi:10.1089/jwh.2012.3602
Acknowledgement
Hess, R, Thurston, R. C., Hays, R. D., Chang, C.-C. H., Dillon, S.
The authors thank Julianne A. Hazard, RN, BS for her assistance with focused literatures searches.
N., Ness, R. B., . . . Matthews, K. A. (2012). The impact of menopause on health-related quality of life: Results from the STRIDE longitudinal study. Quality of Life Research, 21, 535– 544. doi:10.1007/s11136-011-9959-7 Keenan,
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