INTRODUCTION
The typical “mature woman” is aged 40 years or older and has completed childbearing. During their late 40s, most women enter menopausal transition. Detailed in Chapter 21, this period of physiologic change due to ovarian senescence and estrogen decline is usually completed between ages 51 and 56. Menopause marks a defining point in this transition and is defined as the point in time of permanent menstruation cessation due to loss of ovarian function. Clinically, the menopause refers to a point in time that follows 1 year after cessation of menstruation.
With ovarian senescence, declining hormone estrogen levels have specific effects. Some lead to physical symptoms, such as vasomotor symptoms and vaginal dryness, whereas others are metabolic and structural changes. These include bone loss, skin thinning, fatty replacement of the breast, lipoprotein changes, and genitourinary atrophy. As a result, postmenopausal women have unique issues associated with aging and estrogen loss that may negatively affect their individual health.
For many years, menopause was seen as a “deficiency disease” of estrogen, progesterone, and testosterone. For this reason, hormone replacement therapy has been used in one form or another for more than 100 years. The history surrounding this treatment is discussed here, as are current recommendations for the treatment of menopausal symptoms.
HORMONE TREATMENT: HISTORY AND CONTROVERSIES
Clinicians ideally provide evidence-based medicine, and seldom is a single study relied on solely to guide practice (Lobo, 2008). Thus, providers should understand the weaknesses and strengths of clinical trials to accurately counsel their patients. As one example, hormone treatment (HT) was widely prescribed to menopausal women, in good faith, based on initial observational studies. The general medical consensus was that HT, in addition to its prevention and treatment of osteoporosis, could protect against cardiovascular disease, stroke, and dementia. Subsequently, prospective, randomized controlled trials (RCTs) challenged the validity of these earlier observational studies. However, in this evaluation, clinicians must appreciate the type of population studied, the ages and risk factors of participating women, and the hormone regimens tested.
Estrogen treatment (ET) for menopausal symptom relief gained popularity in the 1960s and 1970s. Proponents promoted ET for its “preservation of youth” and prevention of chronic disease. By the mid-1970s, more than 30 million prescriptions were written for estrogen each year, and half of all menopausal women were using ET for a median of 5 years. Premarin (conjugated equine estrogen) was the fifth most prescribed drug in the marketplace.
In 1975, a study revealed a connection between endometrial cancer and ET. Investigators found a 4.5 times greater risk of this cancer in those using estrogen (Smith, 1975). As a result, the Food and Drug Administration (FDA) ordered labeling changes to state this higher risk. Progestins were then added in the 1980s to therapy regimens to significantly reduce endometrial cancer risks.
During that same time, estrogens were documented by several studies to prevent bone loss (Gambrell, 1983). Additionally, an expanding literature provided a robust affirmation of the effectiveness of menopausal HT in reducing vasomotor symptoms, maintaining bone mineral density (BMD), and preventing and treating vulvovaginal atrophy (Shulman, 2010). Several observational studies also suggested that estrogens prevented development of coronary heart disease (CHD) and other conditions, such as Alzheimer disease. However, in 1985, conflicting reports from two studies were published.
First, the Framingham Heart Study, an observational study of 1234 women, showed that those who took hormones had a 50-percent elevated risk of cardiac morbidity and more than a twofold risk for cerebrovascular disease (Wilson, 1985). In the same edition of the New England Journal of Medicine, a much larger observational trial, The Nurses’ Health Study, with 121,964 women, found significantly lower rates of heart disease in postmenopausal women taking estrogen compared with a similar cohort not taking estrogen (Stampfer, 1985). Numerous subsequent articles reported the protective effects that combination HT provided menopausal women against cardiovascular disease and osteoporosis.
Current thinking is that that these early nonrandomized, unblinded, observational studies included samples of women who were not necessarily representative of the entire postmenopausal population. These hormone users tended to have superior access to care and to be thinner, wealthier, and healthier (Grodstein, 2003; Prentice, 2006). An additional source of confounding and possible selection bias is suggested to be the timing of HT initiation relative to the underlying state of the vasculature. Some investigators suggest that estrogen may delay the onset of the earliest stages of atherosclerosis, which are more likely to be present in younger women. However, estrogen may be ineffective or even trigger events in advanced lesions that are found in older women (Mendelsohn, 2005). This potential “window of opportunity” is supported by animal and laboratory studies (Grodstein, 2003). In sum, these study biases may have contributed to favorable outcomes attributed to estrogen in observational trials. When these biases are eliminated and the data reanalyzed, the results of earlier observational trials and later RCTs are remarkably similar.
Because of data available in the late 1980s, estrogens were prescribed, not only for vasomotor symptom relief, but also for prevention of other conditions. In 1995, The Writing Group for the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial published results that suggested benefit for CHD risk. In this study, menopausal women with a mean age of 56 years were randomly allocated to one of five treatments: (1) placebo, (2) estrogen alone, (3) estrogen plus cyclic medroxyprogesterone acetate (MPA), (4) estrogen plus cyclic micronized progesterone, or (5) estrogen plus continuous MPA. Primary outcomes studied in the 875 women evaluated during 3 years included measurement of systolic blood pressure and of serum lipid, insulin, and fibrinogen levels. The PEPI trial documented that low-density lipoprotein (LDL) cholesterol levels declined and high-density lipoprotein (HDL) levels were increased in the four treatment groups receiving estrogens. Levels were most substantially improved in women solely given estrogen. An intermediate effect was noted in those prescribed conjugated equine estrogen (CEE) and micronized progesterone, whereas the smallest change followed CEE and MPA administration. Fibrinogen levels were increased in the placebo group compared with groups given hormones. However, no differences were identified in systolic blood pressure or glucose-challenged insulin levels. Clinical outcomes were also reported, and complications were few. Of these, all occurred in the HT-treated groups and included one cardiac arrest, two myocardial infarctions (MIs), and two cerebrovascular events.
With results published in 1998, the Heart and Estrogen/Progestin Replacement Study (HERS) described cardiac morbidity in 2763 women with preexisting heart disease (Hulley, 1998). These women received estrogen as secondary prevention for further cardiac disease progression. First-year findings showed an increase in MIs in women who received CEE with continuous MPA. However, after average treatment duration of 4 years, rates of cardiovascular death or nonfatal MI did not differ between treatment groups.
This trial represented the first RCT at variance with prior data and created confusion for both clinicians and their patients. Beliefs that hormones prevented heart disease persisted, but the HERS data caused many investigators to question the cardioprotective effects of hormones. Subsequent HERS II results also showed that HT was not beneficial in the secondary prevention of heart disease even after 6.8 years (Grady, 2002). One reanalysis of the Nurses’ Health Study focused on early hazard among women initiating HT during the monitoring period and showed a similar time trend, with early harm (Grodstein, 2001).
After an unsuccessful effort in 1990 to obtain FDA approval for HT as prevention for CHD, the need for RCTs to demonstrate conclusive benefit was widely acknowledged. As a result, before the results from the PEPI trial and HERS trials were available, the National Institutes of Health (NIH) launched the Women’s Health Initiative (WHI) in 1993. This major study was to evaluate the putative protective effects of HT on common chronic diseases of aging. The WHI examined the effect of a single combined CEE and MPA drug compared with placebo in 16,608 healthy postmenopausal women aged 50 to 79 years (mean of 63.3 years) who had not undergone hysterectomy (Rossouw, 2002). Specific end points were evaluated: CHD, venous thromboembolism (VTE), breast cancer, colon cancer, and bone fractures. Concurrently, the study also compared CEE with placebo in postmenopausal women without a uterus (the estrogen-only arm).
As part of the original WHI study design, investigators predetermined targets for CHD (anticipated benefit) and breast cancer (anticipated risk) as primary disease end points. This design dictated that if the incidence of an end point was exceeded within a given period, the study would be terminated. Moreover, combined end points were weighted into a “global index,” which if exceeded, would result in study termination. After a mean 5.2 years of monitoring, the estrogen and progestin arm of WHI was halted early upon recommendation of its Data and Safety Monitoring Board because overall risks exceeded the benefits. In July 2002, results were released to the media. This preceded journal publication of the data and timely education of health care providers. Chaos ensued while physicians and patients evaluated research facts and before recommendations could be made.
In a subsequent detailed analysis of cardiovascular end points, the hazard for cardiovascular death or nonfatal MI was 1.24. This translated into 188 actual cases in the hormone group and 147 in the placebo group (Anderson, 2004). However, there were no significant differences in coronary revascularization, hospitalization for angina, confirmed angina, acute coronary syndrome, or congestive heart failure.
To explore the timing of HT initiation, Rossouw and colleagues (2007) performed a secondary analysis of the WHI data. They looked specifically at the effect of HT on stroke and CHD rates across categories of age and years since menopause in the combined trial. Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause. In women with less than 10 years since their menopause began, the hazard ratio for CHD was 0.76. In those with 10 to 20 years since menopause, the ratio was 1.10; and with 20 or more years, 1.28.
In evaluating data by age, lower risk was found for young women and higher risk for older patients. Specifically, for the age group of 50 to 59 years, the hazard ratio for CHD was 0.93, or two fewer events per 10,000 person years; for the age group 60 to 69 years, 0.98 or 1 fewer event per 10,000 person years; and for those 70 to 79 years, 1.26 or 19 extra events per 10,000 person years. HT increased the stroke risk—the hazard ratio was 1.32—and this risk did not vary significantly by age or time since menopause. Rossouw and colleagues concluded that women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause. Whether CEE or combined CEE and MPA administration improves the cardiovascular health of women who recently experienced menopause remains to be determined. Presently, evidence is insufficient to suggest that either of these regimens should be initiated or continued for primary or secondary CHD prevention (American College of Obstetricians and Gynecologists, 2013). Although this was the principal analysis conclusion, the results led providers and patients to limited HT use, even for healthy women with bothersome vasomotor symptoms during menopausal transition.
Concurrent with the WHI, a similarly constructed study, the Women’s International Study of Long Duration Oestrogen after Menopause (WISDOM), began enrollment in 1999. This trial was stopped following halting of the WHI. Analyzing data collected from this study, Vickers and coworkers (2007) found that HT increases cardiovascular and thromboembolic risk when started many years after the menopause.
With this background in mind, data from no single trial can be extrapolated to all women. In the North American Menopause Society’s (2012) hormone therapy position statement, they note that while the WHI is, for some outcomes, the only large long-term RCT of postmenopausal women using HT, the trial has several characteristics that limit generalization to all postmenopausal women. These include the use of only one formulation of estrogen and only one progestin. Unlike most HT studies that focused on symptomatic, recently postmenopausal women, the WHI enrolled generally healthy but older postmenopausal women. These parameters should be accounted for when applying the WHI findings to clinical practice.
CURRENT HORMONE REPLACEMENT ADMINISTRATION
As a result of these and other studies, most clinicians agree that HT is associated with an increased risk of CHD in older menopausal women, and an increased risk of breast cancer, stroke, VTE, and cholecystitis. Breast cancer appears only to be a risk factor with long-term use (>5 years). Two studies have shown an increase in ovarian cancer risk with long-term use (>10 years) but not with short-term use (<5 years) (Danforth, 2007; Lacey, 2006). However, other studies have not confirmed this risk (Noller, 2002).
In contrast, several long-term benefits are noted with HT. These include increased BMD and decreased rates of fracture and colorectal cancer. HT’s effects on mortality rates have also been examined. A metaanalysis by Salpeter and associates (2004) pooled data from 26,708 participants to reveal that the mortality rate associated with HT was 0.98. Of note, HT reduced mortality rates in women younger than 60 years but not in women older than 60. These investigators suggest that once CHD is established, HT has no effect in reversing disease progression. Moreover, the incidence of cardiovascular events can potentially increase in older groups due to an increased risk for blood clots. Similarly, Rossouw and colleagues (2007) showed a nonsignificant tendency for the effects of HT on mortality rates to be more favorable in younger than older women.
Based on current literature, HT is indicated only for treatment of vasomotor symptoms and vaginal atrophy and for osteoporosis prevention or treatment. Current guidelines recommend reevaluation of the need for HT at 6- to 12-month intervals. HT is prescribed in the lowest effective dose for the shortest period of time. Accordingly, bone-specific agents would likely be more appropriate in women requiring long-term osteoporosis prevention or treatment.
For women with a uterus, a progestin is combined with an estrogen to lower risks of endometrial cancer. Progestins may be prescribed daily with estrogen, and this dosing is termed continuous therapy. Another suitable continuous oral agent is the combination of CEE plus the selective estrogen-receptor modulator (SERM) bazedoxifene. This is marketed as the drug Duavee.
Instead, HT may be provided in a cyclic regimen. For this, estrogen is administered for 25 days each month and a progestin added for the final 10 days. Drugs are withdrawn for 5 days and endometrial sloughing and bleeding follows. Another common regimen includes treatment with estrogen continuously with a progestin administered for the first 10 days of each month. Such cyclic therapy is most often used in those during menopausal transition, whereas continuous therapy is usually selected for women following menopause.
Oral progestins are most commonly prescribed, although a progestin-releasing intrauterine device (Mirena) provides another promising option for localized rather than systemic progesterone administration in postmenopausal women (Peled, 2007). In addition, combined estrogen and progestin products are available for either oral or transdermal use. Low-dose combination oral contraceptives are effective in the young perimenopausal woman and have the additional benefit of pregnancy prevention.
Importantly, estrogen is contraindicated or evaluated in women who exhibit conditions found in Table 22-1. Ultimately, the decision regarding whether or not to begin HT is a personal one, to be decided by the patient with guidance from her health care provider.
| Estrogen should not be used in women with any of the following conditions: |
| Undiagnosed abnormal genital bleeding |
| Known, suspected, or history of breast cancer |
| Known or suspected estrogen-dependent neoplasia |
| Active or prior venous thromboembolism |
| Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke or myocardial infarction) |
| Liver dysfunction or disease |
| Known hypersensitivity to the ingredients of the estrogen preparation |
| Known or suspected pregnancy |
| Estrogen should be used with caution in women with the following conditions: |
| Dementia |
| Gallbladder disease |
| Hypertriglyceridemia |
| Prior cholestatic jaundice |
| Hypothyroidism |
| Fluid retention plus cardiac or renal dysfunction |
| Severe hypocalcemia |
| Prior endometriosis |
| Hepatic hemangiomas |
TREATMENT OF VASOMOTOR SYMPTOMS
Common early symptoms of menopause include hot flushes, insomnia, irritability, and mood disorders, which can be caused by vasomotor instability. Physical changes include vaginal atrophy, stress urinary incontinence, and skin atrophy. Long-term health risks that have been attributed to the hormonal changes from menopause include osteoporosis, cardiovascular disease, and, in some studies, Alzheimer disease, macular degeneration, and stroke.
Of these, the most frequent complaint of the menopausal transition is vasomotor symptoms. Also known as hot flushes or hot flashes, their physiology is discussed in Chapter 21. Following menopause, hot flushes are still pervasive and are experienced by 50 to 85 percent of postmenopausal women. Significant distress results for approximately 25 percent of women. Sleep disturbances can lead to lethargy and depressed mood.
The frequency of hot flushes does decrease with time. In the PEPI trial, the percentage of women taking placebo who experienced vasomotor symptoms declined from 56 percent at their entry into the study to 30 percent by their third year in the trial (Greendale, 1998). Freeman and coworkers (2014) found that moderate to severe hot flushes continue on average for nearly 5 years after menopause, and more than one third of women observed for 10 years or more after menopause have these. Fifteen years after menopause, approximately 3 percent of women report frequent hot flushes, and 12 percent report moderate to severe vasomotor symptoms (Barnabei, 2002; Hays, 2003).
Several treatment options are discussed subsequently, and three have FDA approval for this indication. These are systemic estrogen, one selective serotonin-reuptake inhibitor (SSRI), and the combined CEE plus bazedoxifene agent. When deciding among the available interventions for vasomotor symptoms, the safest options are encouraged first, such as lifestyle changes, but may proceed to prescription treatments, as needed. Patient preference, symptom severity, side effects, and the presence of other comorbid conditions will influence treatment options.
Systemic ET is the most effective treatment for vasomotor symptoms, and the value of such treatment has been demonstrated in numerous RCTs (Nelson, 2004). MacLennan and associates (2004) performed a systematic review of 24 RCTs involving 3329 women who had moderate to severe hot flushes. These investigators found that HT reduced the frequency of hot flushes by approximately 18 events per week, that is, approximately 75 percent compared with placebo. The severity of vasomotor symptoms also was reduced significantly. Moreover, in the PEPI trial, all treatment arms were more effective than placebo in reducing vasomotor symptoms. There were no significant differences between specific hormone regimens (Greendale, 1998).
Estrogen can be administered by oral, parenteral, topical, or transdermal routes with similar effects (Table 22-2). Within these groups, several different formulation choices are available. Continuous estrogen therapy is recommended, although doses and route of administration can be changed relative to patient preference. In the United States, oral estrogens are the most popular. Transdermal estrogen patches avoid the liver’s first-pass effect and offer the convenience of less frequent administration (once or twice weekly). The lowest effective dose and duration of therapy are unknown, but this “mantra” is cited by most major menopause organizations for ensuring safety. For treatment of vasomotor symptoms, the FDA has approved all oral estrogen formulations, most transdermal patch formulations, a topical gel, and one intravaginal estrogen product. All systemic HT products except for the ultra-low-dose estradiol transdermal patch (Menostar) have FDA approval for this indication (North American Menopause Society, 2012).
| Preparation | Generic Name | Brand Name | Available Strengths |
| Estrogen | |||
| Oral a | CEE | Premarin | 0.3, 0.45, 0.625, 0.9, or 1.25 mg |
| 17β-Estradiol | Estrace b | 0.5, 1.0, or 2.0 mg | |
| Estradiol acetate | Femtrace | 0.45, 0.9, or 1.8 mg | |
| 10 synthetic estrogens | Enjuvia | 0.3, 0.45, 0.625, 0.9, or 1.25 mg | |
| Transdermal Patch | 17β-Estradiol | Alora b | 0.025, 0.05, 0.075, or 0.1 mg/d (patch applied twice weekly to abdomen or buttock; 8 patches/box) |
| 17β-Estradiol | Climara b | 0.025, 0.0375, 0.05, 0.06 0.075, or 0.1 mg/d (patch applied to abdomen or buttock weekly; 4 patches/box) | |
| 17β-Estradiol | Menostar b | 14 μg/d (patch applied to abdomen weekly; 4 patches/box) | |
| 17β-Estradiol | Vivelle-dot b | 0.025, 0.0375, 0.05, or 0.075, 0.1 mg/d (patch applied twice weekly to abdomen; 8 patches/box) | |
| Transdermal Gel | 17β-Estradiol | Estrogel b | 1 metered dose of gel applied daily to arm (64 doses per 93-g can) |
| 17β-Estradiol | Estrasorb b | Gel from 2 packets applied to legs daily (56 packets/carton) | |
| 17β-Estradiol | Divigel b | 0.25, 0.5, or 1 mg packets Gel from 1 packet applied to thigh daily (30 packets/carton) | |
| 17β-Estradiol | Elestrin b | 1 metered-dose of gel applied to arm daily (30 doses per 35-g container) | |
| 17β-Estradiol | Evamist b | 1 to 3 metered-dose sprays to forearm daily (56 doses per pump) | |
| Vaginal | Estradiol acetate | Femring | 0.05 or 0.1 mg/d (inserted for 90 days) |
| Progestin | |||
| Oral a | MPA | Provera | 2.5, 5.0, or 10.0 mg |
| Micronized progesterone | Prometrium b | 200 mg (in peanut oil) (1 daily for 12 days each 28-d cycle) | |
| Vaginal | Progesterone | Prochieve 4% b | 45 mg |
| Combination preparations | |||
| Oral sequential a | CEE + MPA | Premphase | 0.625 mg CEE (red) plus 0.625 mg CEE/5.0 mg MPA (blue) (28 pills per pack; 14 red & 14 blue) c |
| Oral continuous a | CEE+ MPA | Prempro | 0.3 mg CEE/1.5 mg MPA, or 0.45 mg CEE/1.5 mg MPA, or 0.625 mg CEE/2.5 mg MPA, or 0.625 mg CEE/5 mg MPA (28 pills per pack) |
| 17β-Estradiol + drospirenone | Angeliq | 1 mg E2/0.5 mg drospirenone (28 pills per pack) | |
| 17β-Estradiol + NETA | Activella | 1 mg E 2/0.5 mg NETA, or 0.5 mg E 2/0.1 mg NETA (28 pills per dial pack) | |
| Ethinyl estradiol + NETA | femhrt | 2.5 μg EE/0.5 mg NETA, or 5 μg EE/1 mg NETA | |
| Transdermal continuous | 17β-Estradiol + LNG | Climara Pro | 0.045 mg/d E 2+ 0.015 mg/d LNG (patch applied weekly) |
| 17β-Estradiol + NETA | CombiPatch | 0.05 mg/d E 2+ 0.14 mg/d NETA, or 0.05 mg/d E 2 /0.25 mg/d NETA (patch applied twice weekly to abdomen) | |
| TSEC a | CEE + BZA | Duavee | 0.45 mg/d CEE + 20 mg BZA |
These alone are somewhat effective for daily treatment of hot flushes in women for whom estrogen is contraindicated. However, adverse effects that include vaginal bleeding and weight gain may limit their use. Beyond mild reduction in number of hot flushes, progestins used as agents in combined HT offer only one additional benefit. Namely, they provide essential protection against estrogen-induced endometrial hyperplasia and endometrial cancer in women with a uterus. Clinical trials have shown that progestins provide no meaningful increase in estrogen’s benefits to bone. Moreover, progestins may attenuate estrogen’s beneficial effects on lipids and blood flow and increase the risk for breast cancer.
This SERM combined with CEE was FDA-approved in 2014 for the management of menopausal vasomotor symptoms in women with an intact uterus (Lobo, 2009). As with other SERMs, bazedoxifene (BZA) acts as an estrogen agonist or antagonist, depending on the tissue affected. This combination is called a tissue-selective estrogen complex (TSEC), and its advantage is to combine the benefits of CEE with the SERM’s ability to offset estrogen stimulation of the endometrium and breast. Thus, a progestin is not required. By itself, BZA reduces BMD loss, increases the number of hot flushes, and raises VTE risks. The combination of BZA 20 mg plus CEE 0.45 mg reduces BMD loss and incidence of hot flushes but does not increase VTE rates compared with CEE and MPA. Notably, BZA acts as an antagonist in uterine tissue to prevent the endometrial hyperplasia commonly associated with unopposed estrogen (Pinkerton, 2014).
In the randomized Selective estrogens, Menopause, and Response to Therapy (SMART-2) trial, BZA plus CEE reduced hot flush frequency by 74 percent at week 12 compared with a 51-percent reduction from placebo (Pinkerton, 2009). A secondary efficacy analysis of SMART-2 data assessed sleep parameters and health-related quality of life in 318 women experiencing >7 moderate to severe hot flushes daily. Time to fall asleep, sleep disturbance, and sleep adequacy were improved with BZA plus CEE compared with placebo. This dose also significantly improved the vasomotor function score and the Menopause-Specific Quality of Life (MENQOL) questionnaire score compared with placebo (Utian, 2009). Overall the BZA plus CEE combined agent is well tolerated and effective in treated hot flushes, but its effectiveness relative to HT remains uncertain.
Some women believe that conventional FDA-regulated pharmaceutical estrogens and progestins hold a clear and present danger. Ironically, more is known about the absolute risks and benefits of HT than almost any other class of drugs. Although prescriptions for estrogen and progesterone have declined significantly since publication of the WHI results, the use of “bioidentical hormones” has increased. This term invented by marketers is often used to describe custom-compounded HT products but has no clear scientific meaning (Shifren, 2014). The term now usually refers to compounds that have the same chemical and molecular structure as hormones that are produced in the body.
Custom compounding of HT may combine several hormones (e.g., estradiol, estrone, and estriol) and use nonstandard routes of administration (e.g., subdermal implants). Some of the hormones are not FDA approved (estriol) or monitored, and some compounded therapies contain nonhormonal ingredients (e.g., dyes, preservatives) that some women cannot tolerate. Moreover, custom-compounded formulations have not been tested for efficacy or safety; product information is not consistently provided to women along with their prescription, as is required with commercially available HT; and batch standardization and purity may be uncertain. Thus, these hormones cannot be assumed to be safer than conventional pharmaceutical estrogen or progestins. Several organizations note that conventional FDA-approved HT products are preferred to custom-compounded formulations (American College of Obstetricians and Gynecologists, 2014a; North American Menopause Society, 2012). In conjunction with bioidentical hormones, salivary hormone testing to assist with hormone level adjustment is inaccurate and unreliable (Lewis, 2002; Zava, 1998).
Several nonhormonal therapies are available to treat vasomotor symptoms (Table 22-3). Alternatively, women who are principally bothered by night sweats and sleep disruption may benefit from a trial of sleep medication, and options are listed in Table 1-16. Of vasomotor symptom therapies, SSRIs, selective norepinephrine-reuptake inhibitors (SNRIs), clonidine, and gabapentin have demonstrated benefits compared with placebo (American College of Obstetricians and Gynecologists, 2014b). Of these, only the SSRI paroxetine mesylate (Brisdelle) is FDA-approved for vasomotor symptom treatment.
| Prescription (brand name) | Dose a |
| SSRI | |
| Paroxetine mesylate (Brisdelle) Paroxetine (Paxil) Venlafaxine (Effexor XR) Citalopram (Celexa) Escitalopram (Lexapro) Sertraline (Zoloft) Fluoxetine (Prozac, Sarafem) | 7.5 mg 20 mg 75 mg 20 mg 10–20 mg 50 mg 20 mg |
| SNRI: Desvenlafaxine (Pristiq) Clonidine (Catapres) Gabapentin (Neurontin) | 100 mg 0.1 mg 600–900 mg |
For many, the side effects or relative ineffectiveness of these agents compared with estrogen therapy can limit their routine use for this indication. Moreover, long-term studies with any of these agents for vasomotor symptom treatment are not available.
As noted in Chapter 21, both serotonin and norepinephrine are implicated in modulation of the thermoregulatory setpoint, which is integral to hot flushes. Accordingly, SSRIs have been studied, and in two RCTs, the low-dose mesylate salt of paroxetine (LDMP) was given to postmenopausal women experiencing daily, moderate to severe hot flushes. One study lasted 12 weeks, and the other 24 weeks (Simon, 2013). In both trials, LDMP reduced the weekly frequency of hot flushes compared with placebo, but persistent declines in hot flush severity were less consistent (Carris, 2014). Following initiation, frequency reduction begins as early as 1 week after therapy, and for severity reduction, as early as 2 weeks.
Other SSRIs have also been studied. With venlafaxine extended release (Effexor XR), Evans and coworkers (2005) noted 51-percent fewer hot flushes compared with placebo. Several other trials have compared this same SSRI with gabapentin or with clonidine in breast cancer survivors with hot flushes and also showed symptom benefit from the SSRI (Boekhout, 2011; Bordeleau, 2010; Loprinzi, 2000). Joffe and associates (2014) compared venlafaxine and low-dose estrogen and noted that estradiol reduced hot flushes by 2.3 events daily compared with 1.8 for the SSRI. Both outperformed placebo.
With paroxetine (Paxil) modest improvement in hot flushes are seen compared with placebo. In one RCT, a 20-mg dose lowered hot flush frequency by 51 percent. Stearns and coworkers (2003) evaluated paroxetine CR, 12.5 mg/d and 25 mg/d dosages, compared with placebo. At both dosages, paroxetine led to approximately three fewer hot flushes per day compared with 1.8 fewer per day with placebo.
With citalopram (Celexa), mean hot flush scores were lowered by 37 to 50 percent (Barton, 2010; Kalay, 2007). With escitalopram (Lexapro), two RCTs noted significant improvement compared with placebo (Carpenter, 2012; Freeman, 2011). Of the SSRIs, fluoxetine (Prozac, Sarafem) and sertraline (Zoloft) appear to be less effective (Gordon, 2006; Grady, 2007; Loprinzi, 2002; Suvanto-Luukkonen, 2005).
Of the SNRIs, desvenlafaxine (Pristiq) significantly reduces the number of hot flushes by approximately 60 percent and their severity by 25 percent compared with placebo (Archer, 2009a,b; Speroff, 2008). A 1-year study noted that these improvements persisted (Pinkerton, 2013).
Importantly, benefits of SSRIs are balanced against drug side effects, which can include nausea, headache, diarrhea, insomnia, jitteriness, fatigue, and sexual dysfunction. With the SNRIs, hypertension may also be aggravated (Handley, 2015).
The centrally active α2-adrenergic receptor agonist clonidine (Catapres) has been effective in some clinical trials (Nagamani, 1987). Many of these RCTs specifically evaluated benefits for breast cancer survivors and showed improvement in vasomotor symptoms (Boekhout, 2011; Buijs, 2009; Loibl, 2007). Notably, hypotension, dry mouth, dizziness, constipation, and sedation may limit its use. For many women, low-dose clonidine is ineffective, and thus adequate therapy may require substantially higher doses that may magnify side effects.
Gabapentin (Neurontin) is structurally related to the neurotransmitter γ-aminobutyric acid (GABA), but its exact mechanism of action is unknown. Currently, gabapentin is FDA-approved to treat seizures and neuropathic pain. However, it has extensive off-label use for various other neurologic conditions.
In 2003, Guttuso and colleagues evaluated the use of gabapentin, 900 mg daily, for treatment of vasomotor symptoms. They found a 45-percent reduction in hot flush frequency compared with a 29-percent reduction with placebo. Moreover, Reddy and coworkers (2006) conducted an RCT in which 60 postmenopausal women received gabapentin, 2400 mg/d; oral CEE, 0.625 mg/d; or placebo for 12 weeks. The reductions in the hot flush composite scores for both estrogen (72 percent) and gabapentin (71 percent) were greater than that associated with placebo (54 percent). However, headache, dizziness, and disorientation occurred in almost 25 percent of the women treated with gabapentin.
Phytoestrogens (isoflavones) are plant-derived compounds that bind to estrogen receptors and have both estrogen agonist and antagonist properties. They are found in soy products and red clover. In sum and outlined subsequently, data supporting their effectiveness for vasomotor symptom treatment show no conclusive efficacy (Lethaby, 2013).
With soy products, although the mechanisms of action are not fully understood, they appear to bind to the estrogen receptor. For this reason, one should not assume these dietary supplements are safe for women with estrogen-dependent cancers. That said, sonographic surveillance has not shown increased endometrial thickness or altered lipid profiles in women taking isoflavones (Palacios, 2010; Quaas, 2013; Ye, 2012). For treatment of hot flushes, data supporting isoflavone efficacy are mixed (Albertazzi, 1998; Cheng, 2007; Liu, 2014; Quella, 2000). Moreover, the effects of soy protein found in various food preparations are not bioequivalent. Even soy foods are not necessarily reliable sources of biologically active isoflavones.
Flaxseed or flaxseed oil (Linum usitatissimum) is rich in α-linolenic acid, a form of omega-3 fatty acid. Also known as linseed, flaxseed is touted to reduce vasomotor symptoms. However, data regarding its efficacy for this indication are contradictory (Lemay, 2002; Lewis, 2006; Pruthi, 2012).
Red clover (Trifolium pretense) is a member of the legume family. It contains at least four estrogenic isoflavones and is therefore marketed as a phytoestrogen source. Several studies and analyses, however, have failed to demonstrate an effect over placebo in the treatment of menopausal symptoms (Geller, 2009; Nelson, 2006; Tice, 2003).
Dong quai, also translated as don kwai, dang gui, and tang kuei, is a Chinese herbal medicine derived from the root of Angelica sinensis and is the most commonly prescribed Chinese herbal medicine for “female problems.” Within traditional Chinese medicine practice, dong quai is suggested to exert estrogenic activity. In most studies, however, its benefit cannot be substantiated (Haines, 2008; Hirata, 1997). Notably, dong quai contains numerous coumarin-like derivatives and may cause excessive bleeding or interactions with other anticoagulants. This herbal agent also contains psoralens and is potentially photosensitizing.
Black cohosh (Cimifuga racemosa) is also thought to have estrogenic properties, although its mechanism of action is unknown. In their Cochrane Review, Leach and Moore (2012) found insufficient evidence to support its use for vasomotor symptom relief. Although few adverse effects have been reported, the long-term safety of this product is unknown.
Extracts, tablets, and creams derived from yams are claimed to be progesterone substitutes. Specifically, claims are made that the plant sterol dioscorea is converted into progesterone in the body and alleviates “estrogen dominance.” However, there is no human biochemical pathway for bioconversion of dioscorea to progesterone in vivo.
In contrast, Mexican yam extract contains considerable diosgenin, an estrogen-like substance found in plants. Some estrogen effects might be expected from eating these yam species, but only if large quantities of raw yams are consumed. Yams from the grocery store generally are not the varieties known to contain significant amounts of dioscorea or diosgenin.
Based on the lack of bioavailability, the hormones in wild and Mexican yam would not be expected to have efficacy. Wild yam extracts are neither estrogenic nor progestational, and although many yam extract products contain no yam, some are laced with progestins. There are no published reports demonstrating the effectiveness of wild yam cream for postmenopausal symptoms. Moreover, oral ingestion does not produce serum levels.
In a few studies in breast cancer survivors, vitamin E provided minimal or no vasomotor symptom improvement (Biglia, 2009; Rada, 2010).
Practices that lower core body temperature such as cooling the room, dressing in layers, and consuming cool drinks may temporarily help with night sweats and flushing (American College of Obstetricians and Gynecologists, 2014b). However, behavioral efforts to curb the frequency of hot flushes have no firm support in RCTs. For example, little evidence demonstrates the efficacy of relaxation techniques, acupuncture, exercise, and yoga to control vasomotor complaints (Daley, 2014; Dodin, 2013; Newton, 2014; Saensak, 2014).
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