Jan L. Shifren
Isaac Schiff
• Vasomotor symptoms affect up to 75% of perimenopausal women. Symptoms last for 1 to 2 years after menopause in most women but may continue for 10 years or longer in others.
• Topical vaginal application of low doses of estrogen is an effective and safe treatment of vaginal dryness, dyspareunia, and some urinary symptoms.
• Counseling women to alter modifiable risk factors is important for the prevention and treatment of osteoporosis. Many women have diets deficient in calcium and vitamin D and will benefit from dietary changes and supplementation. Women should receive 1,000 to 1,500 mg of calcium and 400 to 800 IU of vitamin D daily.
• Contraindications to hormone therapy use include known or suspected breast or endometrial cancer, undiagnosed abnormal genital bleeding, cardiovascular disease (including coronary heart disease, cerebrovascular disease, and thromboembolic disorders), and active liver or gallbladder disease. Relative contraindications include high-risk states for the above disorders.
Menopause, the permanent cessation of menstruation, occurs at a mean age of 51 years. Despite a great increase in the life expectancy of women, the age at menopause remains remarkably constant. A woman in the United States today will live approximately 30 years, or greater than a third of her life, beyond the menopause. The age at menopause appears to be genetically determined and is unaffected by race, socioeconomic status, age at menarche, or number of prior ovulations. Factors that are toxic to the ovary often result in an earlier age of menopause; women who smoke experience an earlier menopause, as do many women exposed to chemotherapy or pelvic radiation (1). Women who had surgery on their ovaries or had a hysterectomy, despite retention of their ovaries, may experience early menopause (2). Premature ovarian insufficiency, defined as menopause before the age of 40 years, occurs in approximately 1% of women. It may be idiopathic or associated with a toxic exposure, chromosomal abnormality, or an autoimmune disorder.
Although menopause is associated with changes in the hypothalamic and pituitary hormones that regulate the menstrual cycle, menopause is not a central event, but rather primary ovarian failure. At the level of the ovary, there is a depletion of ovarian follicles, most likely secondary to apoptosis or programmed cell death. The ovary, therefore, is no longer able to respond to the pituitary hormones, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and ovarian estrogen and progesterone production ceases. The ovarian–hypothalamic–pituitary axis remains intact during the menopausal transition; thus, FSH levels rise in response to ovarian failure and the absence of negative feedback from the ovary. Atresia of the follicular apparatus, in particular the granulosa cells, leads to decreased production of estrogen and inhibin, resulting in elevated FSH levels, a cardinal sign of menopause. Antimüllerian hormone (AMH) is produced by small ovarian follicles, so levels decrease with declining ovarian reserve (3). Although still considered experimental, AMH may one day be used as a reliable marker of the menopause transition.
Androgen production from the ovary continues beyond the menopausal transition because of sparing of the stromal compartment. Androgen concentrations are lower in menopausal women than in women of reproductive age. This finding appears to be associated with aging and decreased functioning of the ovary and adrenal glands over time rather than with menopause per se. Menopausal women continue to have low levels of circulating estrogens, principally from peripheral aromatization of ovarian and adrenal androgens. Adipose tissue is a major site of aromatization, so obesity affects many of the sequelae of menopause.
Several staging systems were developed to describe the many changes that encompass the transition from reproductive life to postmenopause. The late reproductive years are characterized by regular menses associated with elevated FSH levels (4).
• Menopausal transition is characterized by elevated FSH levels associated with variable cycle lengths and missed menses, whereas the postmenopausal period is marked by amenorrhea. The menopausal transition begins with variability in menstrual cycle length accompanied by rising FSH levels and ends with the final menstrual period.
• Menopause is defined retrospectively as the time of the final menstrual period followed by 12 months of amenorrhea
• Postmenopause describes the period following the final menses (4).
The pathophysiologic consequences of menopause may be best understood by considering that the ovary is a women’s only source of oocytes, her primary source of estrogen and progesterone, and a major source of androgens. Menopause results in infertility secondary to oocyte depletion. Ovarian cessation of progesterone production appears to have no clinical consequences except for the increased risk of endometrial proliferation, hyperplasia, and cancer associated with continued endogenous estrogen production or administration of unopposed estrogen therapy in menopausal women. The possible effects of declining androgen concentrations that occur with aging are an area of controversy and active investigation.
The major consequences of menopause are related primarily to estrogen deficiency. It is very difficult to distinguish the consequences of estrogen deficiency from those of aging, as aging and menopause are inextricably linked. Studying the effects of estrogen deficiency and replacement in young women with ovarian failure or of drugs that suppress estrogen synthesis (such as gonadotropin-releasing hormone antagonists) helps to distinguish between the effects of aging and estrogen deficiency. These models are imperfect, though, and differ from natural menopause in many ways.
Principal health concerns of menopausal women include vasomotor symptoms, urogenital atrophy, osteoporosis, cardiovascular disease, cancer, cognitive decline, and sexual problems. Options for caring for menopausal women have increased greatly since hormone therapy was first introduced in the 1960s. With respect to hormone use, there are many choices of hormone type, dose, and method of administration. In addition to hormones, estrogen agonist-antagonists, centrally acting agents, and bisphosphonates are available to treat menopausal health concerns. Women are requesting more information on complementary and alternative therapies, which are being studied more carefully. The many options now available make caring for the postmenopausal woman more challenging and more rewarding.
Health Concerns After Menopause
Vasomotor Symptoms
Vasomotor symptoms affect up to 75% of perimenopausal women. Symptoms last for 1 to 2 years after menopause in most women, but may continue for up to 10 years or longer in others. Hot flashes are the primary reason women seek care at menopause. Hot flashes disturb women at work, interrupt daily activities and disrupt sleep (5). Many women report difficulty concentrating and emotional lability during the menopausal transition. Treatment of vasomotor symptoms should improve these cognitive and mood symptoms if they are secondary to sleep disruption and its resulting daytime fatigue. The incidence of thyroid disease increases as women age; therefore, thyroid function tests should be performed if vasomotor symptoms are atypical or resistant to therapy.
The physiologic mechanisms underlying hot flashes are incompletely understood. A central event, probably initiated in the hypothalamus, drives an increased core body temperature, metabolic rate, and skin temperature; this reaction results in peripheral vasodilation and sweating in some women. The central event may be triggered by noradrenergic, serotoninergic, and/or dopaminergic activation. Although an LH surge often occurs at the time of a hot flash, it is not causative, because vasomotor symptoms occur in women who had their pituitary glands removed. In symptomatic postmenopausal women, hot flashes likely are triggered by small elevations in core body temperature acting within a narrow thermoneutral zone (6). Exactly how estrogen and alternative therapies play a role in modulating these events is unknown. Vasomotor symptoms are a consequence of estrogen withdrawal, not simply estrogen deficiency. For example, a young woman with primary ovarian insufficiency resulting from Turner syndrome will have a very high FSH level and low estrogen levels, but she will not experience hot flashes until she is treated with estrogens and then therapy is withdrawn.
Lifestyle interventions may safely decrease vasomotor symptoms. Being in a cool environment is associated with fewer subjective and objective hot flashes, so women experiencing symptoms should be advised to keep the room temperature low and wear light, layered clothing (7). Overweight women and those who smoke have more severe vasomotor symptoms than women of normal weight and nonsmokers. These findings provide additional reasons to encourage women to lose weight and stop smoking (8,9).
Many menopausal women are interested in trying complementary and alternative (CAM) therapies for relief of hot flashes. These are diverse medical and health care products and practices generally not considered part of conventional medicine. Vasomotor symptoms are particularly sensitive to placebo treatments, and numerous nutritional supplements and other interventions claim to relieve hot flashes but are rarely studied in controlled trials (10). Phytoestrogens are plant-derived substances that may act as estrogen agonists-antagonists, with their effects modulated through interactions with the estrogen receptor. Although they decrease hot flash severity and frequency, symptom improvement is similar to that seen with placebo treatment (11). Black cohosh is another popular alternative treatment, with efficacy likely similar to that of placebo (12). Although often recommended, vitamin E (800 IU per day) only minimally reduced hot flashes in a placebo-controlled, randomized, crossover trial (13).
Acupuncture reduced vasomotor symptoms in several studies, although a traditional Chinese medicine approach may be no more effective than shallow or “sham” needling techniques (14). Exercise and paced respiration demonstrated an improvement in hot flashes in several uncontrolled studies, with additional health benefits, including stress reduction. Women may choose to use alternative and complementary therapies for relief of symptoms, but they should be aware that the safety and efficacy of these approaches often are unproven.
Systemic estrogen therapy is the most effective treatment for vasomotor symptoms and the only therapy currently approved by the U.S. Food and Drug Administration (FDA) for this indication(see Table 34.1 for available hormone therapy formulations). Although standard doses are usually effective, younger women and those with recent oophorectomy may require higher doses. Healthy, nonsmoking women in the perimenopausal transition who are experiencing bothersome hot flashes but still menstruating may benefit from oral contraceptives. The supraphysiologic doses of estrogens and progestins in oral contraceptives effectively treat vasomotor symptoms and provide cycle control. Low-dose estrogen therapy also effectively treats hot flashes for many women. Low-dose oral esterified and conjugated estrogens (CE) (0.3 mg daily), oral estradiol (0.5 mg daily), and transdermal estradiol (0.025 and 0.014 mg weekly) often are effective and associated with minimal side effects and endometrial stimulation (15–17). Progestin therapy must be given concurrently if a woman has not had a hysterectomy, although with low-dose estrogen therapy, intermittent progestin treatment may be an option.
Table 34.1 Hormone Therapy Options
Given the known risks, described in detail later in this chapter, hormone therapy should be used at the lowest effective dose for the shortest amount of time that meets treatment goals. The majority of healthy women with very bothersome hot flashes at the time of the menopausal transition will benefit from short-term therapy and be able to wean off hormones after several years of use.
Because vasomotor symptoms appear to be the result of estrogen withdrawal, rather than simply low estrogen levels, if cessation of estrogen therapy is desired, the dose should be reduced slowly over time. Abruptly stopping treatment may result in a return of disruptive vasomotor symptoms. This recommendation is based on clinical experience, as no controlled trials have been performed to examine the optimal way to cease hormone therapy use. One possible approach to stopping therapy is to reduce the dose and dosing interval slowly (e.g., every 2 or 3 months) and let the patient’s symptoms guide the pace at which she discontinues therapy.
When a woman chooses not to take estrogen or when it is contraindicated, other options are available (Table 34.2) (18). Progestin therapy alone is an option for some women. Medroxy-progesterone acetate(MPA; Provera) (20 mg per day) and megestrol acetate (Megace) (20 mg per day) effectively treat vasomotor symptoms (19,20). Several drugs that alter central neurotransmitter pathways are effective. Agents that decrease central noradrenergic tone, such as clonidine (Catapres), decrease hot flashes, although the effect size is not great. Potential side effects include orthostatic hypotension and drowsiness.
Table 34.2 Options for the Treatment of Vasomotor Symptoms
|
Hormone therapy |
|
• Estrogen therapy • Progestin therapya • Combination estrogen/progestin therapy |
|
Nonhormonal prescription medicationsa |
|
• Clonidine • Selective serotonin and norepinephrine reuptake inhibitors • Gabapentin |
|
Nonprescription medications |
|
• Isoflavone supplements • Soy products • Black cohosh • Vitamin E |
|
Lifestyle changes |
|
• Reducing body temperature • Maintaining a healthy weight • Smoking cessation • Relaxation response techniques • Acupuncture |
|
aNot U.S. Food and Drug Administration–approved for treatment of vasomotor symptoms. |
Selective serotonin or serotonin norepinephrine reuptake inhibitors (SSRIs/SNRIs) are effective and are the mainstay of nonhormonal treatment of hot flashes, although none are FDA approved for this purpose. In a double-blind, randomized, placebo-controlled trial of paroxetine CR (Paxil) (12.5 and 25 mg per day), menopausal women with hot flashes experienced a significant reduction in both hot flash frequency and severity (21). Actual hot flash frequency decreased by 3.3 hot flashes per day on paroxetine versus 1.8 on placebo, and the improvement in vasomotor symptoms was independent of any significant change in mood or anxiety symptoms. The most common side effects were headache, nausea, and insomnia. Paroxetine is a potent inhibitor of the cytochrome P450 system (CYP2D6) required to convert tamoxifen to its active form. It should not be used in women with breast cancer who are receiving tamoxifen, as concurrent use may result in a higher rate of breast cancer recurrence. Venlafaxine(Effexor) (75 mg per day), an SNRI, significantly reduced hot flashes in a controlled trial, though the active treatment group experienced significantly more side effects, including dry mouth, nausea, and anorexia (22). Most studies of SSRI or SNRI use for vasomotor symptoms are only short term and not all show an improvement in symptoms. In a double-blind, parallel-group trial of 9 months' duration, there was no significant improvement in hot flashes with either fluoxetine (Prozac) or citalopram (Celexa) (10 to 30 mg per day) compared to placebo (23).
Gabapentin (Neurontin) is a γ-aminobutyric acid analogue approved for the treatment of seizures that reduced hot flash frequency and severity significantly more than placebo in several randomized, double-blind trials(24). Hot flash scores decreased 54% in the women treated with gabapentin (900 mg per day) compared with a 31% reduction in placebo-treated women. Side effects include disorientation, dizziness, and drowsiness. Women who are principally bothered by night sweats and disrupted sleep may benefit from sleeping medication. In a double-blind, placebo-controlled study of peri- and postmenopausal women, the prescription insomnia treatment, eszopiclone, significantly improved sleep and menopause-related symptoms, with a positive impact on next-day functioning, mood, and quality of life (25). The antihistamine diphenhydramine hydrochloride is an inexpensive, over-the-counter sleep aid.
Urogenital Atrophy
Urogenital atrophy results in vaginal dryness and pruritus, dyspareunia, dysuria, and urinary urgency. These common problems in menopausal women respond well to therapy (26). Systemic estrogen therapy is a very effective treatment for vaginal dryness, dyspareunia, and associated symptoms. Low doses of estrogen applied vaginally are preferred to systemic estrogen therapy when vasomotor symptoms are not present, given minimal systemic absorption and increased safety. Low doses of estrogen cream (Premarin, Estrace) (0.5 g) are effective when used only once or twice a week (27). An estradiol vaginal tablet (Vagifem) (10 μg) inserted twice weekly may be less messy and easier to use than estrogen cream. An estrogen-containing vaginal ring (Estring) (7.5 μg per day) is another convenient formulation, which is placed in the vagina every 3 months and slowly releases a low dose of estradiol (28). Studies of the low-dose estrogen vaginal ring and tablet confirm a small increase in serum estradiol and estrone levels, but these levels remain within the normal range for postmenopausal women (29).
Studies of the vaginal tablets and ring of up to 1 years' duration confirmed endometrial safety, but long-term studies on the effects of low-dose vaginal estrogen therapy on the endometrium are not available. Women using vaginal estrogen therapy should be reminded to report any vaginal bleeding, and a thorough evaluation should be performed. Typically, concurrent progestin therapy is not prescribed with low-dose vaginal estrogenpreparations. Long-acting vaginal moisturizers, available without a prescription, are an effective nonhormonal alternative for treating symptoms of urogenital atrophy when used two to three times weekly (e.g., Replens, KY-Long Acting). Nonhormonal vaginal lubricants (e.g., Astroglide, KY-Silk) increase comfort with intercourse.
Vaginal estrogen therapy appears to reduce urinary symptoms, such as frequency and urgency, and reduces the likelihood of recurrent urinary tract infections in postmenopausal women (30). The effect of estrogentherapy on urinary incontinence is unclear. Whereas the results of some studies suggest improvement in incontinence with estrogen therapy, others show a worsening of symptoms (31).
Osteoporosis
Low bone mass and osteoporosis affect an estimated 30 million US women, or approximately 55% of women older than age 50 years (32). Because therapy is most likely to benefit those at highest risk, it is important to review a woman’s risk factors for osteoporosis when making treatment decisions. Bone mineral density screening should be considered for high-risk women (Table 34.3). Nonmodifiable risk factors include age, family history, Asian or Caucasian race, history of a prior fracture, small body frame, early menopause, and prior oophorectomy. Modifiable risk factors include smoking, decreased intake of calcium and vitamin D, and a sedentary lifestyle. Medical conditions associated with an increased risk of osteoporosis include anovulation during the reproductive years (e.g., secondary to excess exercise or an eating disorder), chronic renal disease, hyperparathyroidism, hyperthyroidism, and diseases requiring systemic corticosteroid use.
Table 34.3 Risk Factors for Osteoporosis
|
Nonmodifiable |
|
• Age • Race (white, Asian) • Small body frame • Early menopause • Prior fracture • Family history of osteoporosis |
|
Modifiable |
|
• Inadequate intake of calcium and vitamin D • Smoking • Low body weight • Excess alcohol use • Sedentary lifestyle |
|
Associated Medical Conditions |
|
• Hyperthyroidism • Hyperparathyroidism • Chronic renal disease • Conditions requiring systemic corticosteroid use |
Assessment
Bone mineral density (BMD) measurements may be used to determine fracture risk, diagnose osteoporosis, and identify women who would benefit from therapeutic interventions. Dual x-ray absorptiometry (DXA) of the hip and spine is the primary technique for BMD assessment. BMD is expressed as a T score, which is the number of standard deviations from the mean for a young, healthy woman. A T score above −1 is considered normal, a score between −1 and −2.5 indicates low bone mass, and a score below −2.5 denotes osteoporosis. Although there is a strong association between BMD and fracture risk, a woman’s age, risk for falls, and overall health status significantly influence fracture risk. Evaluation of BMD by DXA is recommended for all women aged 65 and older, regardless of risk factors, and for younger postmenopausal women with one or more risk factors, other than being white and menopausal (33).
Modifiable Risk
Women should be counseled to alter modifiable risk factors as an important step in the prevention and treatment of osteoporosis. Women with diets deficient in calcium and vitamin D will benefit from dietary modification and supplementation. Daily intake of calcium 1,000 to 1,500 mg and vitamin D 400 to 800 IU is recommended. This may be achieved through a combination of diet and vitamin and mineral supplementation. Treatment with calcium and vitamin D may reduce fracture risk, especially in older women, according to some but not all studies (34–36). Reducing the risk of osteoporosis is another of the many health benefits of regular exercise and smoking cessation. Treatment is indicated for all women with osteoporosis and for those at high fracture risk. FRAX, an online fracture risk assessment tool, provides the 10-year probability of a major osteoporotic fracture for an individual woman (37,38).
Treatment
Drugs used in the prevention and treatment of osteoporosis are principally antiresorptive agents that reduce bone loss and anabolic drugs that stimulate new bone formation (Table 34.4). Hormone therapy effectively prevents and treats osteoporosis. In observational studies, estrogen therapy started soon after menopause and continued long term reduces osteoporosis-related fractures by approximately 50% (39). The Women’s Health Initiative (WHI) trial confirmed a significant (34%) reduction in hip fractures in healthy women randomized to hormone therapy (conjugated estrogen 0.625 mg per day) after a mean follow-up of 5.6 years (40). Combined with calcium and vitamin D, even very low-dose estrogen therapy (conjugated estrogen 0.3 mg per day; transdermal estradiol 0.014 mg per day) produces significant increases in bone mineral density compared with placebo (41).
Table 34.4 Options for Osteoporosis Prevention and Treatment
|
Bisphosphonates |
|
Alendronate (Fosamax) (35 or 70 mg/week orally) |
|
Risedronate (Actonel) (35 mg/week or 150 mg/month orally) |
|
Ibandronate (Boniva) (150 mg/month orally or 3 mg/every 3 months intravenous) |
|
Zoledronic Acid (Zometa) (5 mg/year intravenous) |
|
• Additional potential benefits: none • Potential risks: esophageal ulcers, osteonecrosis of jaw (rare), atypical femoral fractures (rare) Zoledronic acid: hypocalcemia, atrial fibrillation, renal impairment • Side effects: gastrointestinal distress, arthralgias/myalgias |
|
Hormone Therapy |
|
Estrogen or Estrogen/Progestin Therapy |
|
• Additional potential benefits: treatment of vasomotor symptoms and urogenital atrophy • Potential risks: breast cancer, gallbladder disease, venous thromboembolic events, coronary heart disease, stroke • Side effects: vaginal bleeding, breast tenderness |
|
Estrogen Agonists-Antagonists |
|
Raloxifene (Evista) (60 mg/day orally) |
|
• Additional potential benefits: reduced risk of breast cancer • Potential risks: venous thromboembolic events • Side effects: vasomotor symptoms, leg cramps |
|
Other |
|
Calcitonin (Miacalcin) (200 IU/day intranasally or 100 IU/day subcutaneously or intramuscularly) |
|
• Additional potential benefits: none • Potential risks: none • Side effects: rhinitis, back pain |
|
Forteo (Teriparatide) (20 μg/day subcutaneously) |
|
• Additional potential benefits: none • Potential risks: osteosarcoma (after long-term use in rodents), hypercalcemia • Side effects: musculoskeletal pain |
|
Prolia (Denosumab) (60 mg subcutaneously every 6 months) |
|
• Additional potential benefits: none • Potential risks: rash, serious infection, hypocalcemia • Side effects: musculoskeletal pain |
Bisphosphonates, including alendronate (Fosamax, 35 or 70 mg orally weekly), risedronate (Actonel, 35 mg weekly or 150 mg orally monthly), ibandronate (Boniva, 150 mg orally monthly or 3 mg every 3 months intravenous), and zoledronic acid (Zometa, 5 mg intravenous yearly) specifically inhibit bone resorption and are very effective for both the prevention and treatment of osteoporosis(42–44). Patients should take oral bisphosphonates on an empty stomach with a large glass of water and remain upright for at least 30 minutes. The major side effect is gastrointestinal distress; esophageal ulceration, osteonecrosis of the jaw, and atypical femoral fractures are very rare occurrences.
The estrogen agonist-antagonist raloxifene (Evista, 60 mg per day orally) prevents vertebral fractures in women with low bone mass and osteoporosis, though does not appear to reduce the risk of nonvertebral fractures (45). Raloxifene exercises estrogen-like actions on bone and lipids without stimulating the breast or endometrium. Calcitonin nasal spray (Miacalcin, 200 IU per day intranasal) is another approved treatment for established osteoporosis. Unlike most treatments for osteoporosis that inhibit bone resorption, parathyroid hormone (human recombinant PTH 1–34) (teriparatide, Forteo, 20 μg per day subcutaneously) stimulates new bone formation, resulting in significant reductions in vertebral and nonvertebral fractures (46). Recently approved for the treatment of postmenopausal osteoporosis, denosumab (Prolia) 60 mg, a monoclonal antibody to the receptor activator of nuclear factor-κB ligand, decreases the risk of vertebral and hip fractures in postmenopausal osteoporotic women when given subcutaneously twice yearly for 36 months' duration (47).
Cardiovascular Disease
Cardiovascular disease (CVD) is the leading cause of death for women, accounting for approximately 45% of mortality. Nonmodifiable risk factors include family history and age. Modifiable risk factors include a sedentary lifestyle, obesity, and smoking. Medical conditions associated with an increased risk of heart disease include diabetes, hypertension, and hyperlipidemia. Advising women to alter modifiable risk factors for CVD and adequately treating diabetes, hypertension, and hyperlipidemia are important parts of the comprehensive care of midlife women.
As epidemiologic studies identify an approximately 50% decrease in coronary heart disease (CHD) in woman who use hormone therapy, prevention of heart disease was considered a potential benefit of postmenopausal hormones (48). This observed reduction in CHD was considered secondary to beneficial effects of hormone therapy on the vascular wall and lipid levels (49). Observational studies are prone to bias, and women who used hormone therapy were generally healthier and at lower risk for CHD than nonusers (50).
The WHI randomized controlled trial of combination hormone therapy versus placebo showed that hormone therapy did not prevent heart disease in healthy women, but instead, it increased the risk of cardiovascular events in older women (51). The WHI was a 15-year study sponsored by the National Institutes of Health that examined ways to prevent heart disease, osteoporosis, and breast and colorectal cancer in women. There were several different studies in WHI, involving more than 160,000 healthy postmenopausal women. The WHI randomized controlled trial enrolled approximately 16,000 women nationwide between the ages of 50 and 79 years. The average age of women in the study was 63 years. The major goal of the WHI clinical trial was to determine whether combined estrogen and progestin hormone therapy prevented heart disease and to evaluate associated benefits and risks. After an average of 5 years of follow-up, risks (hazard ratio) were increased for CHD (1.3), breast cancer (1.3), stroke (1.4), and pulmonary embolism (PE) (2.1), and decreased for hip fracture (0.7) and colorectal cancer (0.6) (51). The absolute excess risk per 10,000 woman-years attributable to hormone therapy was small, with seven more CHD events, eight breast cancers, eight strokes, and eight pulmonary embolisms, with six fewer colorectal cancers and five fewer hip fractures.
Approximately 11,000 women without a uterus participated in a separate WHI study and were randomized either to estrogen alone or placebo. After an average follow-up of 7 years, there was no increased risk of heart disease or breast cancer in estrogen users. Outcomes were similar to those seen in the estrogen plus progestin arm of WHI with respect to venous thromboembolism, stroke, and osteoporotic fractures; there was no effect on colorectal cancer (52) (see Table 34.5 for a summary of WHI findings).
Studies confirmed that the increased risk of CHD in WHI occurs principally in older women and those who are a number of years beyond menopause (Table 34.6). In a secondary analysis of data from the combined WHI trials, no increased risk of CHD was seen in women between the ages 50 to 59 or in those within 10 years of menopause (53). Although stroke was increased with hormone therapy, regardless of age or years since menopause, the absolute excess risk of stroke in the younger women was minimal. These data do not support a
Table 34.5 Summary of Women’s Health Initiative Study Results
|
Risks per 10,000 Woman-Years Attributable to Estrogen Plus Progestina |
|
|
Excess Risk |
Additional Cases |
|
Coronary heart disease |
7 |
|
Stroke |
8 |
|
Pulmonary embolism |
8 |
|
Invasive breast cancer |
8 |
|
Dementia (WHIMS) (subset older than age 65) |
23 |
|
Reduced Risk |
Fewer Cases |
|
Hip fracture |
5 |
|
Colorectal cancer |
6 |
|
Risks per 10,000 Woman-Years Attributable to Estrogen Alone (Hysterectomized Women)b |
|
|
Excess Risk |
Additional Cases |
|
Stroke |
12 |
|
Deep venous thrombosis |
6 |
|
Reduced Risk |
Fewer Cases |
|
Hip fracture |
6 |
|
No Difference |
|
|
Coronary heart disease |
|
|
Invasive breast cancer |
|
|
Colorectal cancer |
|
|
WHIMS, Women’s Health Initiative Memory Study. aFrom Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333; and Shumaker S, Legault C, Rapp S, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA 2003;289:2651–2662. bFrom Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701–1712. |
|
Table 34.6 Absolute Excess Risk of Coronary Heart Disease and Mortality
role for hormone therapy in the prevention of heart disease, but they do provide reassurance regarding the safety of hormone therapy use for bothersome hot flashes and night sweats in otherwise healthy women at the time of the menopausal transition.
The WHI trials examined treatment only with conjugated equine estrogens and medroxyprogesterone acetate. The effects of other oral estrogen agents, transdermal estradiol, therapy with other progestins, or cyclic hormone therapy may be different. In observational studies, transdermal estrogen therapy is not associated with an increased risk of venous thromboembolic disease (54). The average age of women participating in these trials was more than 15 years beyond the age at which women typically initiate hormone therapy for the treatment of vasomotor symptoms. It is possible that early initiation of hormone therapy may result in a more favorable risk–benefit profile.
The effects of the estrogen agonist-antagonist raloxifene on CHD was studied in a multicenter, randomized trial of approximately 10,000 older postmenopausal women with heart disease or multiple risk factors. Compared with placebo, raloxifene had no significant effect on death from any cause, coronary events, or total stroke, though risk of fatal stroke and venous thromboembolic disease was increased (55). The risks of clinical vertebral fractures and invasive breast cancer were significantly reduced.
Breast Cancer
Breast cancer is a major health concern for menopausal women, as it is the most common cancer in women and the second leading cause of cancer death (56). The lifetime risk of invasive breast cancer for US women is 12%; therefore, any therapies that increase or reduce this risk will have a major impact on women’s health. Risk factors for breast cancer include age, family history, early menarche, late menopause, and prior breast disease, including epithelial atypia and cancer. Risk is reduced in women who had bilateral oophorectomy or a term pregnancy before the age of 30. Many of these risk factors are consistent with the hypothesis that prolonged estrogenexposure increases breast cancer risk.
Long-term use of hormone therapy, generally defined as greater than 5 years, is associated with an increased risk of breast cancer (relative risk [RR] = 1.3) in observational studies (57). There is no increased risk of breast cancer in past users of hormone therapy. The results of several studies suggest that the risk of breast cancer associated with the use of estrogen alone may be lower, with a higher risk in users of estrogen plus progestin (58). The WHI randomized controlled trial demonstrated a significant (26%) increase in the risk of invasive breast cancer after approximately 5 years of use of hormone therapy (51). In women with a prior hysterectomy, there was no increased risk of breast cancer after an average of 7 years of use of estrogen alone (52).
Hormone therapy should not be prescribed to women with a history of breast cancer and should be used by women at high risk only after a very careful assessment of potential benefits and risks.A randomized trial of hormone therapy use in women with a history of breast cancer and bothersome hot flashes was stopped after only 2 years, as more new breast cancers were diagnosed in woman randomized to hormone therapy (59).
The estrogen agonist-antagonist tamoxifen (Nolvadex, 20 mg per day orally) is used in the treatment of estrogen-receptor positive breast cancer. Both tamoxifen and raloxifene reduce the risk of breast cancer in high-risk women by approximately 50% and are approved for this indication (60). The risk of venous thromboembolism is increased approximately threefold with the use of tamoxifen and raloxifene, similar to the increase seen with hormone therapy. Tamoxifen acts as an estrogen agonist in the endometrium, increasing the risk of endometrial polyps, hyperplasia, and cancer, whereas no endometrial stimulation is seen with raloxifene. Performing a screening mammography examination annually for women older than age 50 years reduces breast cancer mortality. Monthly breast self-examination is advised.
Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia. Women are at greater risk for developing the disease than men, and the number of affected individuals in the United States is estimated to be more than 5 million with an annual cost of 183 billion dollars. Although several small studies suggest that hormone therapy may decrease the risk of Alzheimer’s disease, a randomized controlled study in women with mild to moderate Alzheimer’s disease showed that 1 year of estrogen therapy neither slowed disease progression nor improved cognition (61). The WHI Memory Study (WHIMS) was a randomized placebo-controlled study of women aged 65 years or older enrolled in WHI, which assessed the effect of hormone therapy on cognitive function. In contrast to observational studies, women in WHIMS randomized to hormone therapy experienced a significant twofold increased risk of dementia, most commonly Alzheimer’s disease (62). Hormone therapy use was associated with an adverse effect on cognition, as women randomized to hormone therapy scored significantly lower on the Modified Mini-Mental State Examination compared with placebo-treated women (63). Given the increased incidence of stroke identified in hormone therapy users in the WHI trial, it is possible that small, undetected cerebrovascular events were more likely to occur in the hormone therapy group, increasing the risk of dementia.
Hormone Therapy Use
For a healthy woman with bothersome hot flashes, hormone therapy remains a very reasonable option, especially if she is within 10 years of menopause or less than age 60. Hormone therapy should be used at the lowest effective dose for the shortest duration consistent with treatment goals (64–66). The need for continued hormone therapy use should be assessed at least annually.
The use of unopposed estrogen is associated with an increased risk of endometrial hyperplasia and cancer. Therefore, combination estrogen-progestin therapy is recommended for all women with a uterus. Treatment may be provided in a sequential manner, with estrogen daily and progestin for 12 to 14 days of each month, or in a continuous-combined fashion with estrogen and a lower dose of progestin daily. Sequential regimens result in regular, predictable vaginal bleeding. The majority of women using continuous-combined regimens will experience amenorrhea by the end of 1 year of therapy, but the bleeding that does occur is irregular and unpredictable. Low-dose combination hormone therapy products (e.g., Prempro 0.45/1.5 and 0.3/1.5 mg per day) generally result in a lower incidence of breakthrough bleeding and breast tenderness (67).
Women using low doses of oral or transdermal estrogens may elect intermittent progestin use (e.g., 14 days every 3 to 4 months) (68), although these are not approved regimens. A progestin-containing intrauterine device approved for contraception in premenopausal women provides endometrial protection in estrogen-treated menopausal women, although it is not approved for this indication(69). Increased endometrial surveillance is advised with these alternative regimens.
Transdermal administration of estradiol with a patch, spray, or gel may be preferred by some women. Avoiding the “first pass hepatic effect” of oral estrogens on lipids, binding globulins and clotting factors may have benefits for women on thyroid replacement or those with low libido (70). In contrast to oral administration, transdermal estradiol does not appear to increase the risk of venous thromboembolic events or gallbladder disease, though it remains contraindicated in women at high risk for venous thromboembolic disease or those with active liver or gallbladder disease.
Popularized by the media, many women are interested in using “bioidentical hormones” for treatment of menopausal symptoms. Bioidentical generally refers to hormones structurally identical to “natural” hormones made by the ovary, including estradiol and progesterone. FDA-approved oral and transdermal estradiol products are available in a wide range of doses, as is an oral form of micronized progesterone(Prometrium, 100 to 200 mg per day). Progesterone should be taken at bedtime, as it may cause drowsiness. There is potentially significant increased risk and no known benefit to the use of custom-compounded bioidentical hormone therapy formulations, preparations that are “custom” mixed and packaged by a compounding pharmacist for an individual patient (see Table 34.1 for approved hormone therapy formulations).
Contraindications to hormone therapy use include known or suspected breast or endometrial cancer, undiagnosed abnormal genital bleeding, cardiovascular disease (including coronary heart disease, cerebrovascular disease, and thromboembolic disorders), and active liver or gallbladder disease. Relative contraindications include high-risk states for the above disorders. These situations require a thoughtful assessment of potential risks and benefits and documentation of informed patient consent before treatment.
Sexual Dysfunction
Sexual problems are highly prevalent, reported in approximately 40% of US women, with 12% reporting a sexual problem associated with personal distress (71). Although sexual problems generally increase with aging, distressing sexual problems peak in midlife women (aged 45 to 64) and are lowest in women 65 years or older. The etiology of female sexual dysfunction is often multifactorial, including depression or anxiety, relationship conflict, stress, fatigue, prior abuse, medications, or physical problems that make sexual activity uncomfortable, such as endometriosis or atrophic vaginitis. The impact of the menopausal transition on sexual function was examined in a prospective, longitudinal cohort study of approximately 3,000 women who were pre- or perimenopausal at baseline and followed for 6 years. Pain during sexual intercourse increased and sexual desire decreased over the menopausal transition, but other factors were unaffected, including sexual arousal, frequency, and pleasure (72). In contrast to menopausal factors, which were unrelated to most aspects of sexual functioning, age, social, health, and psychological factors were strongly linked.
Treatment Options
Hormone Therapy
Estrogen therapy is very effective in treating vaginal dryness and dyspareunia; however, a significant effect of estrogen therapy on sexual interest, arousal, and orgasmic response, independent from its role in treating menopausal symptoms, is not supported by evidence. A woman with distressing low libido concurrent with the onset of bothersome night sweats, sleep disruption, and fatigue likely will experience increased sexual interest with effective treatment of her menopausal symptoms, but this is probably secondary to improved well-being, rather than a direct effect of estrogen therapy on libido. A double-blind, randomized trial of combined oral and vaginal estrogen therapy in 285 sexually active postmenopausal women demonstrated decreased dyspareunia and significant improvements in pleasure of orgasm and sexual interest in women treated with estrogen therapy compared to placebo (73). As this trial used a combination of systemic and vaginal estrogens, it is not possible to determine the relative impact of systemic versus local effects.
In contrast to estrogen therapy, androgen therapy is consistently shown to improve sexual function in selected populations of postmenopausal women (74–76). Potential risks of androgen therapy include hirsutism, acne, irreversible deepening of the voice, and adverse changes in liver function and lipids. As most androgens are aromatized to estrogens, there is potential for an increased risk of cardiovascular events or breast cancer. A transdermal testosterone patch is approved in Europe for the treatment of hypoactive sexual desire disorder in surgically postmenopausal women using concomitant estrogen therapy. An advisory panel of the FDA did not recommend approval in the United States pending additional data on long-term safety.
Alternatives to Hormone Therapy
Although vaginal atrophy and dyspareunia respond very well to estrogen therapy, most other sexual problems may be effectively treated without hormones. Relationship quality and conflict, stress, and fatigue predict sexual satisfaction, so couples often benefit from counseling, lifestyle changes, and prescribed “date nights.” Women and their partners should be referred to sex therapists who provide education, materials, counseling, and instruction in specific exercises (77). In one study, 65% of 365 couples undergoing sex therapy for a range of sexual dysfunctions described their treatment as successful (78). Underlying depression and anxiety should be treated, and antidepressant medication may need adjustment. Bupropion may be an alternative to SSRIs, and one small, double-blind study reported increased sexual pleasure, arousal, and orgasm in nondepressed women with distressing low desire treated with bupropion (79). Sildenafil citrate may benefit women who develop problems with arousal and orgasmic response on SSRIs but generally is no more effective than placebo for most female sexual problems (80,81).
Despite the fact that sexual problems are common, the majority of women with distressing sexual problems do not seek formal care, but when they do, it is typically the woman, rather than the physician, who initiates the conversation (82,83). Clinicians should routinely ask their menopausal patients whether vaginal dryness, dyspareunia, or another bothersome sexual problem is present, as many effective interventions are available.
Summary
There are many options available to address the health and quality of life concerns of menopausal women. The primary indication for hormone therapy is the alleviation of hot flashes and associated symptoms. Women must be informed of the potential risks and benefits of all therapeutic options. Care should be individualized based on a woman’s medical history, needs, and preferences.
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