Redonda G. Miller
Each year more than 31 million women in the United States experience menopause. These women frequently present to primary care clinicians with a number of symptoms related to estrogen deficiency, as well as with the need to deal with the psychosocial issues related to midlife changes in family and social relationships. Menopause occurs on average at age 51 years, but may occur earlier in smokers (1). Given the increasing life expectancy in the United States, the average woman can expect to spend more than one third of her life in the postmenopausal years.
Because several chronic diseases associated with aging are first manifested at menopause, this is an opportune time for the primary care clinician and patient to assess risk and initiate preventive strategies for cardiovascular disease, osteoporosis, and cancer, in addition to addressing the symptoms of menopause. That assessment has been made more difficult by recent studies that have suggested that some of these diseases might be adversely affected in some women by hormone therapy (HT), the most effective treatment for menopausal vasomotor symptoms (see http://www.hopkinsbayview.org/PAMreferences). These issues are discussed below.
P.1785
Definition and Physiology
The menopause is defined as the last menses. This is a clinical diagnosis that can be determined with certainty only when menses have been absent for 12 months. Perimenopause is the span of time that encompasses the period of initial menstrual irregularity, typically 2 to 8 years before menopause, the menopause itself, and the year subsequent to the menopause. Perimenopause usually begins in the forties, but it is not uncommon for women to experience symptoms as early as their thirties.
During perimenopause, a host of hormonal changes occur. Ovarian follicles undergo progressive atresia over the course of a woman's lifetime, with a consequent gradual fall in circulating estradiol. There is also a loss of production of the glycoprotein inhibin by the ovaries. Inhibin provides negative feedback to the pituitary gland, and, in its absence, pituitary production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increases. An FSH level greater than 30 mIU may support the diagnosis of menopause, but the level tends to fluctuate significantly throughout the perimenopause and is not reliably diagnostic. Routine measurement of FSH, therefore, is not recommended. On the other hand, FSH measurement is useful in certain situations, such as in a hysterectomized woman without classic vasomotor symptoms or a woman who may be experiencing premature ovarian failure.
Because both estradiol and FSH have large fluctuations during this period, the diagnosis of perimenopause is often made clinically, with the onset of menstrual cycle irregularity in a woman with previously regular menstrual cycles. Menstrual irregularity can take the form of shortened cycles, missed cycles, or irregular spotting. Some patients have regular cycles up until the point of menopause. A perimenopausal woman should be cautioned that pregnancy is a possibility until she has been amenorrheic for more than 1 year or until FSH levels have consistently been greater than 30 mIU.
Women may consult their primary care clinicians during this period for concerns about abnormal uterine bleeding or amenorrhea. Patients with abnormal vaginal bleeding (see Chapter 101) should be referred immediately for evaluation. Amenorrhea in women younger than 50 years of age should be evaluated with a pregnancy test. Thyroid dysfunction can also affect the menstrual cycle and should be assessed by screening tests in women who present with menstrual irregularities.
Clinical Considerations
Clinical guidelines (see http://www.hopkinsbayview.org/PAMreferences) for management of menopause generally recommend that the office evaluation of the menopausal patient include a comprehensive risk assessment and screening, as well as attention to the common symptoms of estrogen deficiency (Table 106.1).
|
TABLE 106.1 Office Evaluation of the Perimenopausal Patient |
|
|
The severity of menopausal symptoms is highly variable and is related to both physiologic and cultural factors. Some women are quite debilitated, whereas others have minimal or no symptoms. As an example, a prospective study of 478 Australian women from premenopause to
P.1786
postmenopause found that the number of women reporting five or more symptoms increased by 14% from early to late menopause. Lower estrogen levels, smoking, and a history of no occupation predicted vasomotor symptoms. Insomnia, which increased throughout the menopause, was related not only to hot flashes but also to psychosocial factors (2).
Regardless of initial symptom severity, there are many long-term effects of estrogen deficiency on bone, heart, and breast, which should be evaluated in every patient.
Vasomotor Symptoms
Vasomotor symptoms are the most common reason women seek medical care during perimenopause. These symptoms are usually most common in the first 2 to 3 years of perimenopause and then taper off gradually. The prevalence varies by culture. Up to 75% of women in the United States and Europe experience hot flashes, whereas only 20% of Asian women do. In migration studies of Japanese women, the incidence of hot flashes approached the overall U.S. incidence within one or two generations, which implicates nongenetic factors, such as diet (3). The intensity and frequency of hot flashes are also variable and are usually more severe in women who undergo surgical menopause.
The hot flash is a sensation of heat that typically develops in the head and neck region and then slowly spreads down the arms and across the chest. Intense diaphoresis and visible flushing may accompany the hot flash. Occasionally women may experience a prodrome of nausea, light-headedness, or palpitations. The episode may end with chills and a feeling of coldness. The entire event usually lasts between 30 seconds and 5 minutes. Hot flashes frequently occur at night, leading to lack of sleep and subsequent daytime fatigue and irritability. Other triggers of hot flashes include spicy food, caffeine, alcohol, stress, humid environments, and sexual activity. In a study of African American and Caucasian women, significant predictors of hot flashes were higher FSH levels, anxiety, alcohol use, body mass index, and parity; there was no difference by race (4).
|
TABLE 106.2 Therapies for Menopausal Vasomotor Symptoms |
|||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
The exact cause of hot flashes is unknown, but they may be related to alterations in the hypothalamic thermoregulatory center that are precipitated by a lack of estrogen and increasing gonadotropin levels. Documented increases in skin conductance and peripheral temperature and a subsequent fall in core temperature coincide with the flash (5). Studies using an ingested telemetry pill found that the thermoneutral zone, that is, the range of core body temperature within which sweating, peripheral vasodilatation, and shivering do not occur, is virtually nonexistent in symptomatic women but normal in asymptomatic women (6). Central sympathetic activation is increased in symptomatic women and also reduces the thermoneutral zone in animals. The beneficial effect of clonidine for hot flashes may relate to its reduction of central sympathetic activation.
Treatment
Simple measures can help women cope with hot flashes. Wearing layered clothing permits adjustments for temperature. Regular exercise and avoidance of known triggers can help with prevention. Table 106.2 lists common therapies for vasomotor symptoms, of which estrogen replacement is the most effective. It has been shown to decrease hot flashes by >90% and improve night-time insomnia. Both oral and transdermal estrogens (see later discussion)
P.1787
are effective and work within 1 to 4 weeks. Newer options for estrogen delivery that are effective in reducing hot flashes include a topical emulsion applied daily and an intravaginal estradiol ring inserted by the patient every 3 months (7). Most women respond to standard doses, but occasionally higher doses are required (often in women with an abrupt, surgical menopause). Lower doses of estrogens, now more popular in the wake of recent concern about the adverse effects of estrogen, have demonstrated efficacy for the treatment of hot flashes (8).
For women who are unable or unwilling to take estrogen, other alternatives are available, but none is as effective as estrogen. Progestins alone by oral, topical, or injectable routes may provide effective relief, but often with undesirable consequences such as weight gain. Furthermore, long-term safety of progestational agents for treatment of hot flashes has not been established. The antihypertensive agents clonidine and methyldopa are moderately effective in controlling vasomotor symptoms, but side effects of drowsiness, constipation, and dry mouth may be limiting. Estrogen's interaction with serotonergic and dopaminergic neurotransmitters has led to the use of one class of antidepressants, selective serotonin reuptake inhibitors (SSRIs) (see Chapter 24). Clinical trials of paroxetine, venlafaxine, and fluoxetine found reductions in hot flash scores of 50% to 60%, with associated improvement in sleep and depression (9, 10, 11). Gabapentin, a gamma-aminobutyric acid analog used for the treatment of seizures, has also been shown to be efficacious for vasomotor symptoms, possibly through its effect on hypothalamic tachykinin activity. A dose of 900 mg/day resulted in a 54% reduction in hot flush score (12). Gradual titration of dose is necessary to prevent side effects (see Table 106.2).
Finally, herbal preparations may provide a benefit in the treatment of vasomotor symptoms. Many women prefer herbals as a more natural alternative than prescription medication, and food supplements are being heavily marketed in the United States. The most studied agents are black cohosh and soy protein.
Black cohosh (Actaea racemosa) is a North American herb used by Native Americans and thought to have estrogenic properties. As with many herbal preparations, the safety and efficacy of this substance are not well established (see Chapter 5). A systematic review (13) yielded mixed results, and one randomized controlled trial in breast cancer patients found no benefit of black cohosh over placebo for treatment of hot flashes (14). A standardized extract of black cohosh is marketed as Remifemin and frequently prescribed in Europe.
Phytoestrogens are plant steroids that bind to estrogen receptors, although with much less affinity than human estrogen. They exhibit both estrogenic and antiestrogenic effects. Isoflavones, one of three types of phytoestrogens, are thought to have the most estrogenic activity. Isoflavones are found in soy, chickpeas, lentils, and beans. There appears to be individual variation in the physiologic response to ingestion of isoflavones, but they are relatively well tolerated except for moderate gastrointestinal distress. Although some small studies of soy protein found statistically significant reductions of hot flushes with supplementation, the clinical significance was small, approximately one hot flash per day (15,16). Larger, placebo-controlled trials have not documented any benefit (17,18). Isoflavones may favorably affect the lipid profile by increasing high-density lipoprotein (HDL) and decreasing low-density lipoprotein (LDL) cholesterol levels, but recent studies have suggested no improvements in bone mineral density (19) and a possible risk of long-term endometrial hyperplasia with use over 5 years (20). Therefore, it is difficult to endorse long-term use of these agents.
Urogenital Symptoms
After menopause, the urogenital tract undergoes significant changes and atrophy. Although the exact role of estrogen is unknown, estrogen receptors are located throughout the urogenital tract, and the decline in estrogen levels often correlates with the development of symptoms. Symptoms can be highly variable in character and onset. Some women experience vaginal dryness, itching, and burning. Dyspareunia and loss of libido may be sequelae. Up to one third of women develop urinary incontinence, usually with a stress pattern (see Chapter 54). Estrogen receptors are also found on the pelvic musculature and ligaments, and the decline in estrogen may lead to uterine and bladder prolapse. Other factors that further increase the risk of prolapse include advancing age and history of multiple births. Finally, estrogen plays a role in maintaining vaginal acidity by allowing lactic acid–producing bacilli to flourish. Without estrogen, the flora may shift to bacteria such as Escherichia coli, leading to more frequent urinary tract infections (UTIs). All of these symptoms may occur within the perimenopause or may take up to 10 years to manifest. Many women never approach their primary care provider about this problem because of embarrassment or the misconception that these symptoms cannot be treated.
Treatment
Estrogen is effective in alleviating many of the urogenital symptoms. It improves vaginal dryness, atrophic vaginitis, and dyspareunia. Estrogen has also been shown to lessen the symptoms of urinary incontinence in perimenopausal women (21), but seems to have no benefit and possibly worsens urinary incontinence in older women (22) (see Chapter 54). Postmenopausal women with recurrent UTIs can prolong time to recurrence by using estrogen (23).
Lower doses of estrogen are needed for the relief of genitourinary symptoms than for vasomotor symptoms (Table 106.3). Local delivery of estrogen can result in high tissue
P.1788
levels and is often adequate. Numerous preparations of local estrogen therapy are available today. They include creams (conjugated equine estrogens, estradiol, and diethylstilbestrol), estriol pessaries, and estradiol rings and tablets. All seem comparable in effectiveness, so patient preference plays a large role in choice. Both creams and pessaries, however, can be messy to administer and result in discharge. On the other hand, the vaginal ring and estrogen tablets are well tolerated and only rarely result in mild leukorrhea. Given the low doses used, local estrogen administration is relatively safe and does not seem to result in endometrial hypertrophy. Most preparations do not, however, confer the added benefit on vasomotor symptoms, lipid profile, and bone density that systemic administration does.
|
TABLE 106.3 Therapies for Vaginal Dryness and Genitourinary Symptoms |
|||||||||||||||||||||
|
Cognition and Depression
Women may experience many cognitive symptoms during the perimenopause. Many women describe difficulty with concentration, poor memory, and feelings of sadness or depression. It remains controversial whether these symptoms are truly related to menopause or perhaps are related to the loss of sleep and fatigue associated with nocturnal hot flashes. Another possibility is that they are a reaction to the changes in a woman's cultural roles that may be associated with menopause. Data supporting these hypotheses are conflicting. One longitudinal analysis of more than 2,500 women found no relationship between menopause and depression (24), but another large, cross-sectional study suggested that postmenopausal women using estrogen alone were at decreased risk for depression (25). The second study, however, found no decrease in risk of depression risk among women using both estrogen and progestin.
Sexual Dysfunction
A loss of libido is another frequent concern described by perimenopausal and menopausal women. The lack of interest in sex is probably multifactorial. Depression and low self-esteem, vaginal dryness and dyspareunia, and a decline in testosterone levels may all play a role. Some experts promote the addition of androgens to estrogen therapy to improve libido (26). Testosterone can be delivered as methyltestosterone, 1.25 to 2.5 mg/day; as micronized testosterone, 2.5 to 5.0 mg/day; or with a transdermal patch, 150 to 300 µg/day. Androgens can also prevent postmenopausal bone loss. The side effects of excessive androgen use include acne, hirsutism, alopecia, and voice deepening. Androgens may lower HDL levels, potentially worsening cardiovascular risk. The American Association of Clinical Endocrinologists practice guidelines (27) suggest four situations in which androgen plus estrogen therapy may be considered: (a) oophorectomized women, (b) women who have experienced inadequate relief of vasomotor symptoms with estrogen, (c) women who are at risk for osteoporosis and unable to take other therapies, and (d) women with unsatisfactory sexual function, especially loss of libido. The North American Menopause Society (NAMS) in 2005 concluded that the only indication for testosterone therapy in postmenopausal women is to treat decreased sexual desire in women, finding no other use supported by the evidence (28). In addition to the concerns noted above, the NAMS recommends that clinicians who use testosterone for this indication understand that dosage forms used to treat men have not been tested in women and may be supraphysiologic. For that reason, smaller dosages should be used and blood testosterone levels monitored. Large, randomized trials examining the benefits of adding androgen therapy to estrogen in postmenopausal women do not yet exist. Chapter 101 discusses female sexual dysfunction.
Cardiovascular Changes
The leading cause of death among American women is coronary heart disease (CHD). Before menopause, the rate of myocardial infarction in women is much lower than in men, but by the eighth decade the rates have equalized. Much of the premenopausal protection from CHD in women has been attributed to estrogen.
P.1789
There are several effects of estrogen on the cardiovascular system. The most obvious effect is on the lipid profile. Within 6 months of the menopause, total cholesterol and LDL cholesterol begin to increase. HDL cholesterol levels fall as a result of the estrogen deficiency. This is particularly important in women, because low HDL seems to be a stronger predictor of CHD death in women than in men. Other changes that take place with menopause are increased levels of plasminogen activator inhibitor type 1 (PAI-1), lipoprotein(a), and homocysteine. Each of these is thought to be an independent risk factor for CHD.
Observational studies have demonstrated a protective effect of estrogen on cardiovascular disease. Estrogen appears to decrease the risk of CHD and CHD death in postmenopausal women by 40% to 60% (29). Estrogen may exert much of its protective effect through changes in the lipid profile. Oral estrogen increases HDL cholesterol by roughly 15% and decreases LDL cholesterol by up to 19% (30,31). Triglycerides are also increased, but usually not to a large degree. Addition of a progestin, such as medroxy-progesterone acetate, to estrogen attenuates the beneficial effects on lipids but does not eliminate them (31). With norethindrone acetate use, LDL is still lowered, but there does not seem to be a beneficial increase in HDL. Micronized progestin may be least detrimental on the lipid profile. Estrogen may have other favorable effects on the cardiovascular system. Evidence suggests that it decreases levels of PAI-1, lipoprotein(a), and homocysteine. There is also literature to support a direct vasodilatory effect of estrogen on the coronary vasculature.
The role of estrogen replacement therapy in secondary prevention of CHD was not supported by clinical trials. In the first randomized, controlled trial, the Heart and Estrogen/Progestin Replacement Study (HERS), postmenopausal women with established CHD had similar rates of MI and CHD death whether they were treated with hormone replacement or not (32). Analysis of time trends in the study revealed an excess of events in the estrogen-treated group in year 1 but fewer events in years 4 and 5. This may represent a manifestation of the early prothrombotic effects of estrogen (with increased early events) followed by more long-term beneficial changes. Alternatively, high-risk women may have cardiac events early, leaving only lower risk women in the study. These findings were further backed by the Women's Health Initiative Study. In over 16,000 women with an average age of 63 years, conjugated equine estrogen (CEE) + medroxy-progesterone (MPA) did not confer protection against cardiac events (33). Likewise, CEE alone did not reduce cardiac outcomes in the estrogen-only arm (34). Speculation exists about whether these patients already had subclinical atherosclerotic disease given their age or whether the duration of the study (5.2 years) was insufficient to show a benefit; furthermore, it is unclear how to apply these findings from an older population roughly 12 years past menopause to younger, perimenopausal women. Regardless, the American Heart Association (AHA) has concluded that HT should not be initiated for the secondary prevention of cardiovascular disease and that there is insufficient evidence for its use in primary prevention (35).
Osteoporosis
Osteoporosis is a large health problem that remains underdiagnosed. An average 50-year-old white woman has up to a 50% chance of sustaining an osteoporotic fracture in her lifetime (36). Hip fractures alone are associated with a significant mortality rate of 20% at 1 year. Other sequelae of fracture include difficulty with ambulation, dependence on assisted living, chronic pain, and loss of quality of life. The most rapid loss of bone mineralization occurs in the years after menopause. After 30 years of age, most women experience a loss of approximately 0.5% to 1.0% of their bone density per year. In the first 5 years after menopause, the rate accelerates to 3% to 5% per year before returning to the baseline rate. Prevention of perimenopausal bone loss is therefore crucial. Serial yearly height measurements in the office may provide an early clue to the development of osteoporosis. The loss of 1 inch or more in height is highly suggestive of the disease.
All perimenopausal women should be counseled regarding proper dietary calcium intake. The National Osteoporosis Foundation recommends that postmenopausal women consume at least 1,200 mg/day, or 1,500 mg/day if frank osteoporosis is present. Women also should be encouraged to pursue weight-bearing exercise, as this has been shown to be helpful in bone density preservation. Chapter 103 discusses osteoporosis and its management more thoroughly.
Summary of Therapeutic Options
Hormone Therapy
HT is not for every woman. The enthusiasm for use of HT for prevention of chronic diseases has been tempered by the sobering results of recent data from the Women's Health Initiative (WHI), the first large, randomized controlled trial of HT in postmenopausal women.
Advantages of Hormone Therapy
Many advantages of estrogen have been discussed. One of the most rapid benefits a woman taking HT experiences is significant relief of vasomotor symptoms. Hot flashes diminish within days to weeks, and no other therapy is as efficacious. Vaginal dryness improves, leading to improved ability to have intercourse. UTIs are less frequent as well.
P.1790
Estrogen plays a significant role in the prevention of osteoporosis and fracture. Use of estrogen at menopause allows a woman to preserve bone density and aids in the prevention of osteoporosis. In women who are already osteopenic or osteoporotic, estrogen serves to increase bone density and decrease the fracture rate by up to 40% to 60%. In the WHI, use of either CEE + MPA or CEE alone resulted in a significant reduction in both vertebral and hip fractures in healthy women who were not necessarily osteoporotic (33,34). More recently, ultra-low doses of estradiol 2.5 mg/day were demonstrated to increase bone mineral density in healthy women older than age 65 years (37).
Estrogen therapy (ET) has also been linked to a decreased rate of colon cancer, perhaps via its effects on bile acids (38). Data from the WHI confirmed a protective effect in both combination and estrogen-only arms (33,34). Other purported but not proven roles of HT include prevention of macular degeneration, lens opacities, tooth loss, age-related hypertension, and skin aging.
Disadvantages of Hormone Therapy
Some of the more prevalent disadvantages of estrogen therapy are the non–life-threatening side effects. Menopausal women starting HT may experience breast tenderness or vaginal spotting. These symptoms tend to resolve within 2 months in most women. Low-dose oral bromocriptine (2.5 mg twice daily) may be helpful in alleviating the breast tenderness on a short-term basis, as may prescribing an estrogen-free period a few days each month. Contrary to popular belief, postmenopausal doses of estrogen are not associated with weight gain.
The biggest fear shared by many women is that estrogen may cause breast cancer. These fears are not unfounded, and many studies have unsuccessfully attempted to put the issue to rest. Given the observational nature of most of these studies, they are confounded by selection and lead-time bias. Two studies are often cited. The Nurses’ Health Study monitored almost 70,000 postmenopausal women and found a relative risk for development of breast cancer of 1.3 to 1.4 among current users of estrogen (39). Duration of use greater than 10 years was highly correlated with the development of breast cancer, and former use was not. Conversely, the Iowa study of high-risk women with positive family histories showed no increased risk, even with use lasting longer than 5 years (40). The WHI has not clarified the issue as much as had been hoped. Women assigned to CEE + MPA had a small increased risk of breast cancer compared to patients taking placebo (HR = 1.24) (33), but women in the CEE-only arm developed fewer cases of breast cancer than did women in the placebo arm (34). No study has definitively shown increased mortality due to breast cancer, leading some experts to postulate that estrogen use may result in “better-differentiated” and less aggressive tumors. Another possibility is that women who use estrogen are more compliant with mammography and more likely to have cancers detected earlier or perhaps it is the use of progestational agents that increase a woman's risk rather than the estrogen component. Estrogen's exact role in the development of breast cancer, therefore, remains controversial.
Studies have repetitively linked endometrial adenocarcinoma to the use of unopposed estrogen in women with an intact uterus. The risk is roughly 2.3 times that of women who do not use estrogen. Risk is related to duration of use. In women using unopposed estrogen for longer than 10 years, the relative risk rises to 9.5 (41). If estrogen is combined with a progestin, the risk is not elevated above that of nonusers. Therefore, use of a progestin with estrogen in nonhysterectomized women should be considered the standard of care. The progestin may be given continuously or cyclically with the same protective benefit. Given that many women will experience some mild vaginal spotting with the institution of HT, one must distinguish this fairly common side effect from a more serious problem. If vaginal bleeding is mild and occurs immediately in an otherwise healthy woman initiating HT, watchful waiting is appropriate. Temporarily increasing the dose of progestin may help alleviate this bleeding. If the bleeding persists beyond 6 months, is particularly heavy, or starts months to years after the initiation of HT, the patient should be further evaluated. A transvaginal ultrasound examination may be helpful in assessing the thickness of the uterine lining and detecting fibroids. Referral to a gynecologist and probable endometrial biopsy is also warranted.
Estrogen therapy has been undisputedly linked to an increased risk of venous thromboembolic disease, and recent WHI data support this association (31,33,34,42). Users tend to have 2.5 to 3.5 times the risk of nonusers. This is less than the risk associated with oral contraceptive use, probably because postmenopausal doses of estrogen are considerably lower than those in oral contraceptives. Estrogen also increases the risk of gallbladder disease in women, albeit only modestly (32). In the liver, estrogen can increase the metabolism and turnover of cholesterol, leading to increased excretion in the bile and subsequent stone formation. This side effect has not been associated with higher mortality.
The absolute contraindications to estrogen are relatively few. Most experts would agree that a personal history of breast cancer and acute thromboembolic disease fall into this category (Table 106.4). Many of the disadvantages listed previously must be taken in context with the patient's individual risks and may be considered relative contraindications, depending on the clinical setting. Some of the relative contraindications can be addressed by alternative delivery; transdermal estrogen avoids the first-pass effect and has some advantages in specific situations (see Available Formulations section).
|
TABLE 106.4 Potential Contraindications to Hormone Therapy |
|||||||||||||||
|
|||||||||||||||
P.1791
Inconclusive Effects of Hormone Therapy
The potential benefits or risks of HT with regard to prevention of cardiac disease remain controversial. As discussed earlier, estrogen exerts favorable effects on the lipid profile and other cardiovascular markers. In the WHI, however, there was no evidence for prevention of CHD, and in fact, an increased incidence of cardiac events occurred in the first year of the combination study. Whether initiation of HT earlier, at the time of menopause (the average age of WHI participants was 63 years) or avoidance of progestins would improve CHD outcomes remains to be proven.
Estrogen's role in the prevention of dementia is also unclear. Estrogen receptors are widespread throughout the body, including the central nervous system (CNS). It has been proposed that estrogen may protect against Alzheimer disease. A published meta-analysis demonstrated that estrogen users had a 29% decrease in the risk of dementia (43), but randomized clinical trials of estrogen in women with established mild-to-moderate Alzheimer disease found no improvement in cognitive performance (44,45). For prevention of the disease in women with no cognitive impairment at baseline, the WHI Memory Study (a subset of the WHI) demonstrated no protective benefit for mild cognitive impairment or dementia, albeit the study duration was short (only 4 and 5 years for CEE + MPA and CEE arms respectively) (46,47).
Some concern has been raised about a possible link between estrogen and ovarian cancer. Earlier studies were inconsistent, but a cohort study of more than 200,000 women suggested that use for longer than 10 years conferred more than twice the risk of mortality from ovarian cancer compared with no use (48). For former users, risk decreased with time. These results must be interpreted cautiously, because many study participants were taking unopposed estrogen; combination therapy is not well studied.
Available Formulations
ET and combination HT may be delivered by several different routes and formulations, each with unique characteristics (49) (Table 106.5). Deciding which to use is often a matter of individual choice and preference. After careful evaluation of the patient and discussion of her concerns, the primary care clinician is ideally suited to tailor a treatment regimen that will best meet the patient's needs (Table 106.6). In a woman without a uterus, estrogen alone can be prescribed without a progestin, because there is no risk of endometrial hyperplasia. In a woman with a uterus, a progestin (synthetic progesterone) must be added to estrogen. There are several ways to do this. The first is to cycle the estrogen and progestin so that monthly sloughing of the endometrium occurs; this is referred to as cyclic combined therapy. This is accomplished by giving the estrogen on menstrual cycle days 1 through 25 and the progestin on days 16 through 25. After day 25, the woman experiences a period. Most women do not like the inconvenience associated with continued menses. A useful alternative is to deliver both the estrogen and the progestin on a continuous daily basis (continuous combined therapy). This method may result in some initial vaginal spotting that usually resolves within 2 to 3 months. Vaginal spotting is most common in women within 1 or 2 years of menopause, and cyclic therapy may be preferable for these women. Increasing the dose of progestin for a period of 1 to 2 months may decrease the amount of bleeding. Many combination products containing various forms of both estrogen and progestin are available and offer the convenience of once-a-day dosing.
Many options exist for choosing an estrogen for an individual patient. Conjugated equine estrogens are the most widely used and studied type, including the form used in the WHI. Other preparations include 17-β-estradiol, esterified estrogens, ethinyl estradiol, synthetic conjugated estrogens, or estropipate. The standard doses used are much lower than those found in oral contraceptives, but they are adequate to restore physiologic status. Young women experiencing surgical menopause often require higher doses of estrogen, as much as 1.25 to 2.5 mg conjugated estrogens per day. If the initial dose is ineffective, escalating the dose for a brief period may be helpful. More recently, low-dose estrogen has become increasingly popular with the hope of limiting adverse effects. Lower doses control hot flashes and improve vaginal atrophy comparably to standard-dose preparations in most patients and preserve bone mineral density (37,50).
Estrogen can be delivered by several routes, including orally, transdermally, or vaginally. Oral administration provides “first-pass” metabolism through the liver and thus offers the most benefit on the lipid profile (increase in HDL, decrease in LDL). Transdermal estrogens are often more convenient, but they lack the metabolic effects in the liver,
P.1792
and consequently have less of a beneficial effect on cholesterol. In a woman with liver disease or high triglycerides, however, this may be desirable. Another potential benefit of avoidance of first-pass metabolism may be less effect on coagulation factors and thus lower thrombotic risk, although definitive evidence is lacking (51). Both oral and transdermal forms are very useful in relieving vasomotor symptoms. Vaginal estrogens are effective locally, providing relief of vaginal dryness and dyspareunia. They have very little systemic absorption: the only vaginal preparation that ameliorates hot flashes is the intravaginal ring inserted every 3 months (52).
|
TABLE 106.5 Forms of Hormone Therapya |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
As with estrogen, the choice of progestin type is one of preference, although there is reason to believe that different progestins may have varying effects and perhaps some are better than others. This is an active area of investigation. All progestins have some detrimental effect on the lipid profile. Micronized progesterone may affect the lipid profile least. MPA is popular because of the potential for less androgenic activity and its availability in combination pills. Norethindrone acetate (also available in a combination preparation) results in the least amount of vaginal spotting and bleeding, but, as noted previously, may not cause the rise in HDL seen with other combinations
P.1793
(52). Delivering progesterone with an intrauterine device (IUD), as in levonorgestrel-releasing intrauterine system (Mirena), has the advantage of providing contraception as well as endometrial suppression for the perimenopausal patient (53).
|
TABLE 106.6 Clinical Considerations when Prescribing Hormone Therapy for Vasomotor Symptoms |
|||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
For postmenopausal women with poor libido, some experts have recommended adding an androgen to the HT regimen. Only limited data from small studies are currently available (26). Other potential benefits of androgen therapy include improved mood and added increases in bone mineral density. HDL cholesterol decreases, however, in contrast to the increase seen with estrogen alone. Other expected androgenic side effects, such as hirsutism, acne, and weight gain, have not been commonly described with the use of low doses of testosterone. In a postmenopausal woman with low libido, a 3- to 4-month trial of androgen therapy is a reasonable approach, keeping in mind that definitive data regarding effectiveness are not available. Adding an androgen to estrogen does not negate the necessity for a progestin in a woman with a uterus.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are a relatively new class of drugs that have both estrogen receptor agonist and antagonist effects, depending on the target organ. Tamoxifen, one of the first SERMs, has been available since 1969. It is used primarily for prevention of recurrent breast cancer. There are several limitations to its use, including a worsening of hot flushes, an increased risk of endometrial hyperplasia and possible adenocarcinoma, and an increased risk of thromboembolic disease. Another commonly used SERM, raloxifene, demonstrates estrogenic effects on bone, the lipid profile, and the coagulation system, and antiestrogenic effects on the breast
P.1794
and uterus. At the approved dose of 60 mg/day, there are several benefits to raloxifene therapy (Table 106.7) (54). Perimenopausal women can expect to gain an average of 1% to 2% in bone mineral density at both spine and hip at 2 years (55). Regarding the lipid profile, total cholesterol declines by 6% to 7% and LDL cholesterol falls by 10% with treatment. In contrast to the effect with estrogen, however, HDL cholesterol also falls by about 3%. How this relates to long-term protection from cardiac events and mortality is currently unknown. Women taking raloxifene do not experience any thickening of the uterine lining or any increase in the incidence of uterine cancer (55). Finally, data from the 7,700 women in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial suggest that raloxifene may play a role in breast cancer prevention, with the observation of a 76% reduction in the risk of invasive cancer in treated women (56). This was not a primary design of the study, however, and additional studies designed to clarify this point are pending.
|
TABLE 106.7 Estrogen versus Raloxifene for Hormone Therapy |
||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
Raloxifene is not without drawbacks. In many women, it leads to onset or worsening of hot flashes. There is also a threefold increase in the risk of thromboembolic disease, comparable to the risk with estrogen.
Despite the lack of a head-to-head comparison, raloxifene is considered a reasonable alternative for the woman who does not want to take estrogen or has a contraindication to its use but who still desires bone protection and lower LDL cholesterol.
Overall Approach to Helping Women Decide about Using Hormone Therapy
Helping a women decide whether to pursue HT for menopause-related symptoms is a complicated task. The controversy around the pros and cons of HT seems to become murkier every day. Although the WHI shed significant light on HT use for the prevention of chronic disease, it is important to remember that neither arm was designed to study newly menopausal women with vasomotor symptoms and, in fact, women with moderate to severe hot flashes were discouraged from enrolling in the trial. The results may not be as relevant to a younger, perimenopausal woman presenting to her caregiver for vasomotor relief. Furthermore, the WHI studied only one preparation and dose of HT and each arm (ET and HT) was of limited duration (5 and 8 years, respectively).
Each woman presenting to her caregiver has a different risk profile for various diseases and certainly different preferences and fears about HT. Women do not always openly express these preferences and fears. In fact, up to 20% of women prescribed estrogen for the first time discontinue it within 1 year, 10% use it only intermittently, and up to 30% never fill the prescription (57). Likewise, in the wake of the WHI, up to 56% of women attempted to discontinue HT, although many experienced significant recurrence of symptoms (58). For these reasons, the clinician must have an extensive and ongoing dialogue with the patient about HT.
An National Insitutes of Health (NIH) Consensus Conference emphasized that menopause should not be labeled a “medical condition” but rather a normal, healthy phase of a woman’ life. Many women make this transition with few or no symptoms and are not in need of medical treatment (59). Women who do experience vasomotor symptoms and seek medical care are reasonably easy to counsel. A useful position statement from The North American Menopause Society suggests that women with mild hot flashes should first attempt lifestyle changes and avoidance of triggers as an initial step. For women with moderate to severe vasomotor symptoms, short-term use of less than 5 years of ET or HT has been shown to be most effective and is the gold standard. Such short-term use appears to have little risk (60). Nonhormonal medications that show some efficacy, such as the antidepressants and gabapentin, are reasonable alternatives. Clonidine and methyldopa are less useful due to higher adverse effects. As for prevention of chronic diseases, both the North American Menopause Society and the U.S. Preventive Services Task Force recommend against the institution of HT for this purpose and encourage clinicians to choose alternative pharmacologic agents to minimize long-term risk of CHD and osteoporosis (60,61).
Many questions remain about HT, but it is clear that HT should not be a universal recommendation for all women. It must be tailored to the individual patient and should involve a discussion of risks and benefits. In some cases, particularly women with severe hot flashes, benefit will outweigh risk. Attempts to model such trade-offs using quality-adjusted life expectancy support short-term use of HT in symptomatic women (62). Much-needed research regarding HT and chronic diseases, different HT formulations and doses, and newer SERMs is ongoing. For now, clinicians should maintain an open line of communication with the patient about menopause and its related issues to ensure a smooth transition into the postmenopausal years.
P.1795
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.1796