Julie A. Elder DO
Barbara J. Messinger-Rapport MD, PHD
Holly L. Thacker MD, FACP
ESSENTIALS OF DIAGNOSIS
DIMINISHED ESTROGEN PRODUCTION
Diminished estrogen production, encountered during menopause, has long-term health implications. Many of the clinical signs and symptoms experienced during the menopausal and postmenopausal years can be directly and indirectly linked to hormonal deficiencies. Various body systems are affected, including vasomotor/neuroendocrine, skin/hair, urogenital, skeletal, and cardiovascular (Table 35-1).
Symptoms & Signs
Women typically encounter hot flashes during the menopause transition and early postmenopausal phase. Other problems include cephalgia, flushing, nausea, and diaphoresis. Women may also experience palpitations, dizziness, and “skin-crawling” sensations. These symptoms of estrogen deficiency persist an average of 5 years. However, up to 25% of women will experience hot flashes beyond this period.
Although menopause does not cause depression, women with previously diagnosed panic disorder or depression may note exacerbations of their disease processes with the onset of the vasomotor symptoms as a result of estrogen deficiency. Appropriate identification of an underlying mood disorder is important because some form of depression occurs in 1-5% of community dwellers older than 65. Older women are more likely to be depressed than older men regardless of race, ethnic background, and economic status. Complaints of helplessness and hopelessness, symptoms of irritability, and findings of cognitive deficits may be more prominent than dysphoria. Left untreated, depression
can lead to cognitive and functional decline and increased overall morbidity.
Table 35-1. Menopausal signs & symptoms.
Systemic estrogen, either oral or transdermal, may relieve vasomotor symptoms. Higher doses of estrogen and, occasionally, the addition of androgens may be required to fully alleviate the symptoms in younger women who have been surgically castrated. Lower doses of estrogen typically suffice in older women, although some may experience inadequate symptom relief. These women may benefit from the addition of methyltestosterone (ie, a combination of esterified estrogen and methyltestosterone).
Estrogen therapy may augment antidepressive therapy and improve quality of life in appropriate candidates (ie, those whose vasomotor symptoms contribute to their depressive symptoms during the menopause transition and early postmenopausal phase). There is also evidence that unopposed estradiol may decrease symptoms of depression independent of vasomotor symptoms. The mechanism by which estradiol reduces depressive symptoms is unclear; however, it modulates neuronal function via noradrenergic, dopaminergic, and gamma-aminobutyric acid-mediated systems.
Symptoms & Signs
Estrogen deficiency is responsible for mucosal dryness in the vagina and possibly in the eyes, nose, and mouth. Some women may complain of skin aging because decreased collagen and elastin production causes a loss of skin elasticity. Approximately 30% of skin collagen is lost within the first 5 years of menopause as a result of estrogen deficiency. Estrogen deficiency results in a relative androgen excess associated with a male-pattern alopecia, hirsutism, and deepening of the upper register of the voice.
Hormone therapy (HT) during the transition and early postmenopausal phase enhances skin thickness, improves vascularization, and increases the life cycle of hair follicles. It also improves the quality and context of collagen. The overall effect may be an improvement in skin texture and enhancement of skin healing.
Symptoms & Signs
Loss of estrogen's stimulation of receptors in the urethra, vagina, and bladder may cause significant dysfunction of the urogenital system. Dysuria, urinary incontinence (UI), increased urinary frequency, and urinary tract infections may result from estrogen deficiency. These symptoms increase in incidence with age.
Sexual dysfunction resulting from dyspareunia and decreased libido may be a problem that women are hesitant to mention. Deficiency of estrogen and androgen may lead to thinning of the vaginal tissues, causing dyspareunia. In addition, the urethra and bladder can become irritated during intercourse and cause recurrent cystitis and urethritis.
Either systemic or topical estrogen can control most urogenital symptoms related to hormone deficiency including dyspareunia, dysuria, urinary incontinence, and sexual dysfunction. Topical vaginal estradiol and estriol, however, are the only hormone regimens that demonstrate a reduction in the frequency of urinary tract infections. Addition of a vaginal estrogen to systemic estrogen therapy may augment the urogenital benefits without requiring an increased systemic dose.
Estrogen plays an important role in the preservation of bone mineral density (BMD). Women begin losing bone mass gradually at ~30 years of age. This decline in bone mass continues with age and accelerates throughout the menopause transition and into the menopause years. In fact, postmenopausal women who are recently estrogen deficient can lose up to 4-5% of their bone mass annually, eventually leading to low bone mass and osteoporosis. Osteoporosis is responsible for 1.5 million low-trauma fractures each year, resulting in considerable morbidity and mortality in the older population. Osteoporosis must be prevented, if possible, and treated once it is diagnosed because the risk of recurrent osteoporotic fractures is high.
Prevention and Treatment
Prevention of osteoporosis begins in childhood with appropriate nutrition, exercise, and weight management. Continuation of appropriate lifestyle habits into midlife and beyond, including sufficient calcium and vitamin D intake, weight-bearing exercise, and avoidance of smoking and excessive caffeine consumption, helps maintain peak bone mass.
The National Osteoporosis Foundation recommends BMD screening for all women older than 65 regardless of race. The optimal interval for bone density screening has not yet been established. However, it is hoped that early intervention will reduce the risk of fractures. Medicare currently covers bone density screening every 2 years in women older than 65.
Calcium intake is an important component of nutrition. Replacement of calcium has been shown to increase bone density in young women and stabilize bone density in postmenopausal women. Postmenopausal women require at least 1200-1500 mg of calcium in split doses plus 400-800 IU of vitamin D daily. Daily ingestion of > 50,000 µg (10,000 IU) of vitamin A should be avoided because of an increased risk for hip fractures.
Oral and transdermal estrogens have been approved by the Food and Drug Administration (FDA) for the prevention of osteoporosis. Other medications that are FDA approved to prevent or treat osteoporosis include bisphosphonates (risedronate, alendronate), selective estrogen receptor modulators (raloxifene), and calcitonin nasal spray (treatment only). Bisphosphonate use is associated with a reduction in hip fractures. Women who begin estrogen in the early postmenopausal phase and continue the regimen for an average of 15 years have demonstrated an 80% decrease in hip fracture rate.
Discontinuation of estrogen may result in a loss of accumulated benefit. If HT is begun during the menopause transition and early postmenopausal phase, it maintains its benefit as long as it is continued. Consideration should, therefore, be given to continuing HT throughout the late postmenopausal phase if bone protection is the goal and the risk-benefit equation for the individual woman warrants long-term treatment. The initiation of estrogen therapy in the late postmenopausal phase has been shown to preserve and even increase bone density. Even low doses of estrogen (eg, 0.3-0.45 mg of conjugated estrogen or 0.5 mg of estradiol-17β) may improve bone density.
Women who are at increased risk for falling should consider wearing hip protector pads, which significantly decrease the incidence of hip fractures. Hip pads cost approximately $100 and can be ordered from Tytex Group. Currently, insurance companies do not cover the cost.
Tytex Group: http://www.safehip.com
Body fat increases and lean body mass decreases with aging. Fat is deposited centrally. Insulin resistance may also develop. These changes, accompanied by an increase in low-density lipoprotein cholesterol (LDL-C) and a decrease in high-density lipoprotein cholesterol (HDL-C), increase the risk of cardiovascular disease. HT decreases LDL-C, increases HDL-C, and decreases insulin resistance. Observational data favor HT in terms of preventing vascular disease and prolonging survival in women. However, it has been shown that a combination of conjugated equine estrogens, 0.625 mg, and medroxyprogesterone acetate, 2.5 mg, failed to reduce coronary artery disease (CAD), nonfatal myocardial infarctions (MIs), and CAD-related deaths in hormone users with known heart disease despite an 11% reduction in LDL-C.
In addition, estrogen and progestin therapies have not be shown to prevent coronary heart disease (CHD) in women with intact uteri. HT should not be used for cardiovascular risk reduction in late postmenopausal women. In fact, HT has been shown to increase the cardiovascular risk, primarily from nonfatal MIs. Currently, the American Heart Association advises against starting or using HT for the prevention of cardiovascular disease in women older than 50.
Systemic Lupus Erythematosus
Lupus is more common in women than in men and appears to have symptom variation with hormonal fluctuations (ie, with pregnancy and the menstrual cycle). It has been suggested that there is a 2.5- to 2.8-fold increased risk of lupus associated with postmenopausal estrogen use.
The incidence and severity of osteoarthritis (OA) increase with age in postmenopausal women. HT may decrease the risk of OA in postmenopausal women, in part, by increasing BMD. High BMD has been associated with a decreased prevalence of knee OA. In addition, a high BMD and a gain in BMD have been associated with decreased risk of knee OA progression.
The decision to begin or continue HT should be based on symptoms and patient preferences, including contemplation of anticipated risks, associated benefits, and choice of agent.
North American Menopause Society: http://www.menopause.org
Complications (Table 35-2)
Systemic HT use increases a woman's relative risk of venous thromboembolism (VTE) by 2- to 4-fold. The absolute VTE risk is very low in young, healthy women and does not translate into a clinically significant risk with hormone therapy use in symptomatic young women. However, VTE risk increases with age and comorbidity. For example, women with an average age of 67 and known CAD have been shown to have ~1 VTE per year for every 260 women treated. Women with prior VTE are at a very high risk for recurrent events.
Table 35-2. Risk & benefits of HT.
Estrogen taken alone (unopposed estrogen) more than doubles the risk of endometrial adenomatous hyperplasia, a precursor for endometrial cancer, in women with intact uteri. The addition of progestin reduces the risk of endometrial cancer to slightly less than the spontaneous occurrence rate of endometrial cancer in non-HT users. Low-dose intravaginal forms of estrogen rarely stimulate the endometrium enough to require progestins. However, higher vaginal doses of estrogen may cause bleeding in 10% of cases, requiring progestin opposition therapy.
Short-term use of HT (< 4 years) does not increase the risk of breast cancer. Epidemiological data suggest that estrogen therapy increases the relative risk of breast cancer after 5 years of therapy. This risk may be amplified with increasing duration of therapy and decreased to baseline after cessation of therapy, suggesting that HT is a growth promoter rather than a carcinogen. The WHI reported an increased risk of breast cancer in hormone-estrogen-progestin users with a hazard ratio of 1.26.
Gallbladder disease is associated with various risk factors, including older age, female gender, obesity, oral contraceptive use, estrogen therapy, and ethnicity. Adequate vitamin C intake may reduce the risk of gallstones in women.
Postmenopausal estrogen may increase the risk of gallbladder disease and cholecystectomy. It has been shown that women with coronary artery disease have a 40% increased risk for symptomatic gallbladder disease and an increased risk of biliary tract surgery while taking HT.
Pregnancy, active venous thromboembolism, undiagnosed vaginal bleeding, active liver disease, unstable cardiovascular syndromes, active breast cancer, and active endometrial cancer are absolute contraindications to HT (Table 35-3).
Relative contraindications include previously treated breast cancer, previously treated uterine cancer, previous thromboembolism, gallbladder disease, uncontrolled hypertension, existing heart disease, migraines, uterine fibroids, seizure disorder, and marked hypertriglyceridemia (see Table 35-3).
Table 35-3. Contraindications to HT.
Systemic estrogen is administered orally or transdermally (Tables 35-4 and 35-5). Intravaginal estrogen therapy with or without standard HT may augment the treatment of urogenital symptoms (Table 35-6). Intravaginal estrogen is available in the form of creams, tablets, and intravaginal estradiol rings. Women usually insert the rings themselves, but the health care provider can assist with insertion and removal if necessary. There is no significant systemic absorption of estradiol with the intravaginal estradiol ring, and it does not stimulate the endometrium. This is an advantage for women with intact uteri who are not using progestins and for those who are suffering from local genitourinary symptoms who do not want or cannot tolerate the systemic effects of estrogen.
The use of intravaginal estrogen creams and tablets may occasionally be associated with systemic absorption, thus stimulating endometrial growth. Evaluation of the endometrium with an endometrial pipelle biopsy is necessary if endometrial stimulation is suspected. A progestin must accompany systemic estrogen replacement to prevent endometrial hyperplasia in women with intact uteri and in some women using vaginal estrogens.
Table 35-4. Oral estrogens.
Oral estrogen is available in multiple forms with variations in the metabolic half-lives between preparations. Estradiol-17β has the shortest half-life and requires split dosing for symptom control. Transdermal estradiol in patch form may benefit women who cannot tolerate or take oral forms because of nausea. It is also beneficial in women with elevated triglycerides because transdermal estradiol does not increase triglyceride levels to the same degree as oral estrogen. A skin gel may soon be available.
The typical starting dose of oral conjugated equine estrogen (CEE) or synthetic conjugated estrogen is 0.3-0.625 mg daily. Doses can be adjusted higher or lower depending on the symptoms after 1 mo of therapy. Younger women who have been surgically castrated may need higher doses of estrogen. Increased use of ultra-low doses of estrogen (such as 0.3 or 0.45 mg of CEE combined with ultra-low doses of medroxyprogesterone acetate [MPA]) is the new standard based on the favorable results regarding control of vasomotor symptoms, metabolic effects, bone benefits, and endometrial bleeding profile in symptomatic early postmenopausal women.
Conjugated equine estrogen has been used clinically for > 6 decades and is commonly used by postmenopausal women. However, some women prefer synthetic forms of conjugated estrogens, or natural, plant-derived, lab-synthesized estrogens that are not derived from animal products. If a woman cannot tolerate conjugated estrogens, other forms of estrogen, such as estrone (E3), micronized estradiol (E2), esterified estrogen, or transdermal 2(estradiol) should be considered. The FDA has approved all postmenopausal estrogens for the treatment of vasomotor symptoms and local genitourinary atrophy. Only some estrogens, however, have been FDA approved to prevent postmenopausal
osteoporosis. Examples include CEE, CEE/MPA, estradiol, and estropipate.
Table 35-5. Transdermal estrogens (estradiol-17β).
Progesterone downregulates estrogen receptors. Progestins are synthetic formulations that are better absorbed than micronized progesterone (Table 35-7). Oral progestins can be taken cyclically (12 days/month) or continuously (daily) at lower doses. For cyclic therapy, 5-10 mg of MPA or 200 mg of micronized progesterone is taken 12 days each month. Micronized progesterone is taken in the evening because of its potentially sedating and hypnotic effects. It is also taken with food to enhance absorption. Heavier and younger women may require larger doses of progestins. Cyclic therapy is usually preferable for recently menopausal women. The goal of cyclic therapy is to switch eventually to continuous combined (daily estrogen and progestin) therapy to promote amenorrhea, which is favored by most women. For continuous estrogen-pro- gestin therapy, 1.5, 2.5, or 5 mg of MPA is taken every day. If ultra-low doses of estrogen are used, lower doses of MPA can be used, such as 1.5 mg of MPA or 100 mg of micronized progesterone daily. The addition of MPA to CEE appears to further enhance the benefits of estrogen in vasomotor symptom control. Progestins and estrogen are also available in combined forms, including a transdermal patch and oral pills (Table 35-8). Cyclic regimens cause withdrawal bleeding in the majority of users, whereas continuous use over 6 mo induces amenorrhea, a desired effect. An endometrial biopsy or a transvaginal ultrasonogram should be performed to assess the endometrial thickness if amenorrhea is not induced after 6 mo of continuous therapy. Endometrial stripes measuring > 5 mm in postmenopausal women are suspicious. Heavy bleeding that lasts > 1 week per month also warrants evaluation of the endometrium. Saline infusion sonography (SIS) can be used to visualize local defects, such as endometrial polyps or asymmetric areas in the endometrium via ultrasonography. Performed in either the outpatient or operative setting by an experienced operator, hysteroscopy provides direct visual information of the endometrium and the uterine cornua. The cornua is not well seen with SIS.
Table 35-6. Intravaginal estrogens.
Most nonmalignant postmenopausal bleeding can be treated with progestin therapy. There are certain circumstances, however, when a hysterectomy is indicated (eg, atypical hyperplasia in women older than 30 and adenomatous hyperplasia without atypia in women who have had persistent uterine bleeding or who have failed progestin therapy). Uterine leiomyomas, pelvic pain, moderate to severe idiopathic uterine bleeding, and uterine hypertrophy may also warrant a hysterectomy.
Table 35-7. Oral progestins.
Controversies of Estrogen Therapy in the Late Postmenopausal Phase
Use of HT in older, asymptomatic women does not show any primary or secondary cardiovascular benefit, whereas symptomatic HT users have experienced cardiovascular risk reduction, primarily in VTE and stroke. Explanations may include inability to control for all variables in the epidemiological data, unknown pharmacogenetic contributions, and particularly the specific hormonal and life phase in which HT is initiated. The data and the controversial underlying issues make the physician's decision to initiate HT in the late postmenopausal phase much more difficult. For the older woman who wants bone protection but has some increased risk for cardiovascular disease, stroke, and breast cancer, other agents besides HT should be considered.
A small percentage of women continue to have vasomotor symptoms in the late postmenopausal phase. Some women who never had perimenopausal symptoms may develop vasomotor symptoms in their 60s and 70s because of an age-related decrease in testosterone production. The aromatization of endogenous testosterone to estradiol may have protected these women from vasomotor symptoms in their early menopausal years. Ultra-low doses of estrogen, such as 0.3 mg of CEE or .025 mg of transdermal estradiol-17β, may be of benefit as a low-dose alternative to the standard dose that a woman is already taking or, if appropriate, as an initial HT regimen. Initiation of HT must be very gradual and in lower doses in postmenopausal women. In older women, hormone therapy can be discontinued when vasomotor symptoms resolve, providing there are no other systemic indications for its continued use.
Table 35-8. HT combination therapy.
Some women may require higher doses of estrogen for vasomotor symptom control beyond the perimenopausal phase, making it difficult to transition to a standard dose of estrogen. In these women, low-dose testosterone allows for maintenance of a relatively low dose of estrogen for symptom control. Continuing testosterone supplementation in the late postmenopausal phase is controversial but can be offered to women with significant vasomotor symptoms who are at lower than average risk for cardiovascular disease. Plasma lipid levels, liver function tests, and clinical evidence of virilization should be monitored periodically during follow-up exams.
Bisphosphonates are the initial therapy of choice for hip fracture prevention in older, late postmenopausal women, although an 80% risk reduction for hip fractures has been demonstrated in women 75 years and older on long-term estrogen therapy. This risk reduction has not been equaled by any other medications, including bisphosphonates.
HT must be continued indefinitely to maintain its benefits. Ideally, the lowest dose of estrogen should be used to minimize long-term VTE and breast cancer risks and maintain osteoporosis protection. Raloxifene, 60 mg daily, may be considered for women with spinal osteopenia or osteoporosis who are at greater-than-average risk for breast cancer. Raloxifene appears to maintain bone density while possibly lowering the risk
for breast cancer. The VTE risk of raloxifene is equivalent to that of estrogen; however, there is no vasomotor benefit and no positive effect on skin or vaginal atrophy. Preliminary data on cognition do not show any increased risk of memory loss associated with raloxifene.
The prevalence of Alzheimer's Disease (AD) increases with age to nearly 50% in ≥ 85 years. Epidemiological studies of HT users compared with nonusers have demonstrated a reduction in risk or a delay in the clinical manifestations of dementia, particularly AD. However, a benefit of HT in women with established AD has not been established, and women who start hormone therapy in the late postmenopausal period may actually have an increased risk of dementia and stroke.
Pharmacogenetics may influence how women respond to HT. The prothrombin gene mutation variant is one example. HT users with hypertension who have this genetic variant have a 10- to 20-fold greater risk for myocardial infarction than HT users who do not carry this genetic variant. Factor V Leiden is another example of a genetic variant that may affect vascular events associated with HT use. However, ~188 women would need to be screened for the factor V Leiden variant and have HT withheld to prevent 1 VTE.
Genetic typing, particularly in combination with BMD testing, may also help identify women at high and low risk of fragility fractures. This insight would help risk-stratify long-term HT use in the late postmenopausal phase for osteoporotic protection. In addition, genetic differences in the estrogen receptor gene have been shown to affect lipids. Women with a specific estrogen receptor-α variant have markedly increased HDL cholesterol and no increase in ultra-sensitive C-reactive protein. It is hoped that pharmacogenetics will help identify women who will benefit the greatest and the least from long-term HT.
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