Menopause

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15

Menopause Anne W. Moulton, MD Mary H. Hohenhaus, MD Michelle Stozek Anvar, MD

Epidemiology More than 30 million women in the United States are now in or past menopause, and another 6 million women will enter menopause during the next decade. The average age of menopause is 51, with a range of 45 to 55. Cigarette smoking, alcohol abuse, some chemotherapeutic agents, and radiation exposure have been associated with earlier onset of menopause. Older menopausal age is seen with increased parity, obesity, and Japanese ancestry. The age of mother’s menopause is a strong predictor for the daughter’s age of menopause. Because the current average female life expectancy is 78 years, a woman can expect to spend more than one-third of her life in the postmenopausal period.

Definitions Menopause is defined as a cessation of ovarian function that results in permanent amenorrhea. Because 12 months of amenorrhea ensures a cessation of ovulation in older women, definitive diagnosis is usually made retrospectively. A standardized system for the chronology and terminology of menopause was developed by a consensus panel in 2001. They defined the menopausal transition as the period of time from the first variation in menstrual cycle length and elevated follicle-stimulating hormone (FSH) to the 34 9

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Practical Gynecology

final menses. Menopause is the year of amenorrhea after the final period. Perimenopause includes the transition phase and menopause itself. Postmenopause includes the remaining lifetime after menopause (1).

Physiology Hormonal changes reflecting a decrease in ovarian function begin to occur in the decade before the development of irregular cycles. As ovarian production of steroid hormones falls, there is a loss of negative feedback at the hypothalamus and pituitary. The earliest laboratory evidence of these enEarly in the perimenopausal transition, docrine changes is a mild increase in FSH levels toward the upper the menstrual cycle interval often limit of normal. There is a conshortens due to a shorter follicular comitant fall in estrogen levels phase. but only a slight decline in progesterone secretion. During the course of the perimenopausal transition, the menstrual cycle interval often shortens (because of a shorter follicular phase), and gradually these cycles become interspersed with abnormally long intermenstrual intervals (secondary to anovulatory cycles). When menstrual cycles cease, the secretion of steroid hormones and gonadotropins changes dramatically. The FSH level rises sharply, and estradiol levels fall. The ovaries continue to produce hormones until women The ovaries continue to reach approximately age 65 (2). produce androstenedione However, they no longer produce until women reach approximately estradiol or progesterone, but age 65. rather the androgen androstenedione, some of which is converted to estrone by peripheral adipose tissue. Androstenedione production is reduced by about 50% after menopause as well (3); however, because of the reduction in estrogen, there is relative androgen excess.

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Cultural Variations There are significant international variations in the development and perception of menopausal symptoms. These differences need to be viewed in light of cultural variations in diet, exercise, and medical illnesses. In cultures with more positive attitudes toward mid-life, women’s menopausal symptoms are reported less frequently.

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In the first large U.S. study of culturally diverse women aged 40 to 55, Japanese and Chinese American women were less likely to report symptoms. White women were more willing to report psychological or psychosomatic symptoms. African-American women were more likely to experience hot flashes. In summary, this study showed that there was no universal menopausal symptom complex, and the study noted substantial variation by race/ethnicity (4).

Short-Term Symptoms Irregular Bleeding Unpredictable vaginal bleeding is one of the most common clinical occurrences during the perimenopausal transition. Most women experience between 2 and 8 years of irregular menses before the onset of menopause. Changes in cycle length and frequency of bleeding are common Perimenopausal women at this time, and are most comfrequently experience monly due to anovulation. Howirregular bleeding; established ever, if an episode of bleeding criteria help determine who occurs more often than every 21 should undergo evaluation. days, is profuse for longer than 7 to 10 days, or occurs after a 6month interval of amenorrhea or in a very irregular pattern, then evaluation for other possible causes is indicated (Box 15-1). Work-up usually includes a pregnancy test, complete blood count (CBC), thyroid-stimulating hormone

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Box 15-1 Irregular Bleeding in a Perimenopausal Woman* When to evaluate: • Episodes of bleeding occur more frequently than every 21 days • Bleeding is profuse for more than 7 to 10 days • Bleeding occurs after a 6-month interval of amenorrhea • Bleeding occurs in a very irregular pattern Evaluation should include: • Pregnancy test as indicated, CBC, TSH • Pelvic examination and Pap smear (if due) • Endometrial biopsy • Pelvic ultrasonography, including evaluation of the endometrial stripe * Evaluation is performed to exclude such etiologies as pregnancy, thrombocytopenia, and hypothyroidism. Also, women in this age group are at increased risk for endometrial hyperplasia and cancer, cervical cancer, endometrial polyps, and leiomyomata (fibroids).

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(TSH), pelvic exam, Pap smear (if due), pelvic ultrasonography, and endometrial biopsy. Referral to a gynecologist is often indicated for endometrial biopsy, or, if this does not provide reassurance, dilation and curettage (D&C)—with or without hysteroscopy. Following a negative evaluation, treatment options often include low-dose combined oral contraceptives, cyclic progestins, or the levonorgestrel-releasing intrauterine device (Mirena), depending on whether the patient smokes or has other contraindications to estrogen, has need for contraception, and other factors (see Chapter 3).

Hot Flashes The most widely acknowledged symptom of menopause is the hot flash, occurring in about 75% of all menopausal women, with a higher percentage noted in perimenopausal women (5). Risk factors for increased frequency and severity of hot flashes include obesity, smoking, sedentary state, and increased stress. Flashes are sometimes triggered by stress, hot weather, confining spaces, or by the ingestion of caffeine, alcohol, or spicy foods. There is increasing evidence that hot flashes result from the physiologic response to a change in the hypothalamic set point (5), possibly as a result of estrogen withdrawal (6). A vasomotor flash has two stages. It begins with a hot flash, which is a sudden transient sensation ranging from warmth to intense heat that spreads over the body, particularly on the upper chest, face, scalp, and head. This is followed by the physiologically measurable hot flash, with Nearly half of menopausal visible erythema and perspiration women experience hot in the same distribution. Hot flashes for over 5 years and, for flashes can be objectively mea- unexplained reasons, 10%-15% sured as changes in skin temperaexperience hot flashes many years ture, diminished skin resistance, after menopause. Hot flashes can and decreased core temperature. sometimes be severe, adversely Some women also experience palaffecting quality of life and pitations and feelings of anxiety. disrupting sleep. The duration of hot flashes ranges from 30 seconds to several minutes, but the frequency and severity are often quite variable between women. Most women remain symptomatic for more than a year. The percentage of women who experience hot flashes for longer than 5 years ranges from 29% to 50%, and for unexplained reasons, about 10% to15% of women continue to have hot flashes many years after menopause (6). There is wide variability in the distress associated with hot flashes. A small percentage of women report severe hot flashes that significantly disrupt sleep and adversely affect quality of life. Treatment is discussed later in this chapter.

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Genitourinary Symptoms The vagina, urethra, and trigone of the bladder have multiple estrogen receptors, and thus are affected by the waning estrogen levels associated with menopause. Unlike other hormonal effects of menopause that diminish over time, genitourinary symptoms can continue indefinitely and often progressively worsen. Because women may be hesitant to report genitourinary symptoms, it is important to screen women for these issues as they result in significant morbidity and can often be easily treated. Beginning in perimenopause, the vaginal walls become thinner and dry, the vagina shortens and narrows, and sebaceous glands secrete less lubrication. Decreased estrogen stimulation results in less glycogen production by the vaginal epithelium leading to a decrease in lactobacilli that metabolize the glycogen. Lactobacilli are responsible for the acidic pH of the vagina, and without them the pH rises to 5.0 or greater, allowing other bacterial species to colonize the vagina. On exam, vaginal walls can appear inflamed, The saline wet mount may have small petechiae, and lose be helpful in diagnosing their rugal folds. A wet mount atrophic vaginitis. The epithelial may reveal few lactobacilli and cells appear smaller and more smaller, more oval-shaped epitheoval-shaped, and fewer lial cells. A Pap smear may demonstrate atrophic cells or lactobacilli are seen. ASCUS (atypical cells of undetermined significance) in postmenopausal women. These changes all point to the presence of atrophic vaginitis. Patients typically note symptoms of dryness, vaginal burning, external dysuria, and dyspareunia. Urinary incontinence is a common issue for postmenopausal women and the incidence increases as women age. A recent study revealed that 66% of women had some degree of incontinence and 8% had severe incontinence; however, only about 45% of women with weekly incontinence reported it to their physicians (7,8). The urinary tract has the same embryonic origin as the genital tract and thus a decline in estrogen is associated with atrophy of the urethral epithelium. Incontinence, however, is not clearly related to estrogen deficiency. Moreover, rather surprisingly, the Women’s Health Initiative (9) and other studies (10) revealed that systemic (but not vaginal) estrogen may worsen urinary incontinence (see Chapters 10 and 16).

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Depression Contrary to previous studies, recent evidence suggests an increase in psychological distress in many women undergoing menopause (11,12). There are

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variable rates of distress within the stages of menopause, with highest rates in early perimenopause. The role of sleep disturbance in psychological distress was significant but does not fully explain the effect of menopause. Relative to white women, the odds of psychological distress were lower for African Americans, lower still for Hispanics, and lowest in Asian women (11). Women with a previous history of depression are at increased risk for depressive symptoms with menopause. Treatment is discussed later in this chapter.

Miscellaneous Symptoms Many symptoms are listed as potentially related to menopause, but research has not established a definite causation for most of them. The long list of symptoms reported during the period extending from perimenopause through menopause includes palpitations, chest pain, headache, fatigue, change in bowel habits, decreased libido, dry skin, formication (the sensation of bugs crawling on the skin), and increasing joint pain.

Long-Term Issues for Postmenopausal Women Osteoporosis Osteoporosis is a diffuse skeletal disease characterized by low bone mass and deterioration of bone microarchitecture that increases skeletal fragility and risk of fracture. More than 7.7 million women over age 50 met bone density criteria for osteoporosis in 2002, and an additional 21.8 million women met criteria for low bone mass or osteopenia; as the U.S. population ages, these numbers are projected to increase to 10.5 and 21.8 million, respectively, in 2020 (13). Although osteopenia carries a lower risk for fracture, the substantially larger population of osteopenic women accounts for a greater absolute number of fractures. Fragility fractures are a major medical problem for women, causing substantial morbidity and mortality, loss of function, and suffering. In 2005, there were an estimated 1.4 million fragility fractures among American women aged 50 years and older, at a total cost of $12.8 billion (14). Of these estimated 1.4 million fractures, nearly one-third occurred at the vertebrae, and substantial proportions occurred at the distal forearm and hip. The lifetime risk of a hip fracture for a 50-year-old white female ranges from 14% to 20%, but an individual woman’s risk varies greatly according to her risk profile (15). Women achieve peak bone mass in their early 30s. Estrogen is an important regulator of bone remodeling, and reduced levels of endogenous estrogens

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are a major contributor to the decline in bone density after menopause. Bone density decreases by 1% per year on average after menopause, although accelerated rates of loss have been described in the years immediately after menopause, as well as among more elderly women. The risk for fracture varies inversely with bone density. However, bone density is not the sole determinant of fracture risk. Other factors include age, personal or family history of adult fracture, low body weight, smoking, sedentary lifestyle, conditions of increased metabolism or malabsorption, and exposure to certain drugs, such as steroids. Falls are an important risk for fragility fracture in elderly women. Decreased muscle mass and strength, poor vision, and impaired balance and reaction time all increase fall risk.

Cardiovascular Disease Cardiovascular (CVD) disease is a major cause of mortality and morbidity for women in the United States. Patients and physicians alike do not appreciate the fact that more women than men die every year from CVD. The majority of women with acute CVD are older than their male counterparts (16). The delay in the development of coronary disease in women has been attributed to the beneficial effects of circulating estrogen before the development of menopause. After menopause, the risk of developing coronary artery disease in women starts to climb, and by age 70 to 80 equals that of men. AfricanAmerican women have higher rates of coronary artery disease, with higher subsequent morbidity and mortality rates as well. Rates of coronary artery disease in Hispanic and Asian women are somewhat lower. Traditional cardiac risk factors (diabetes, hypertension, elevated cholesterol, smoking, positive family history) determine cardiac risk in women as they do for men. The magnitude of the effect of these factors may be different for women, however, and in addition to premature menopause, there may be other gender-specific coronary artery disease risk factors that are yet to be defined.

Evaluation of the Patient The primary care physician should be able to educate and reassure patients about what to expect at menopause, and such counseling should ideally be part of routine primary care visits for women in their late 40s (Box 15-2). The perimenopausal transition is also an appropriate time to review health maintenance and routine preventive measures. The diagnosis of menopause is usually satisfied by an adequate menstrual history along with a brief review of systems. For women who have symptoms suggestive of menopause yet continue to experience fairly regular menses, or

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Box 15-2 Role of the Primary Provider in the Care of the Menopausal Woman Counseling on the average woman’s experience with menopause: • Mean age of 51 • Considerable cultural and individual variation in the experience of menopause • Majority do not have severe symptoms • Risk of depression in menopause Assessment and treatment, as needed, for symptoms: • Screen for menstrual disturbances • Screen for hot flashes, vaginal dryness, sleep disturbance, changes in mood, and quality of life • Screen for urinary incontinence • Screen for personal and family history of estrogen-sensitive cancers if hormone therapy is to be used Establish risk factors for heart disease and osteoporosis: • Assess patient’s medical history, exercise, diet, smoking, alcohol intake • Assess patient’s family history Screening for diabetes, hyperlipidemia, and osteoporosis: • Glucose, fasting lipid panel • Bone densitometry at age ≥65 (or earlier if indicated) Provide resource information: • Web-based educational materials • Books, pamphlets • Community resources/local support groups

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for women who have undergone Menopause is usually hysterectomy, an elevated serum diagnosed with an follicle-stimulating hormone (FSH) adequate menstrual history and may be useful in verifying the brief review of systems. A serum diagnosis. A rapidly changing knowledge FSH is useful for women who base about menopausal symptoms report symptoms suggestive of and treatment necessitates the menopause yet have regular use of resources that provide up- menses, or for those who have dated information on menopause undergone hysterectomy. (see Resource section below). Previously validated scales for assessing menopausal symptoms may be helpful. Scheduling extra visits is often necessary in order to discuss individual symptoms and treatment options along with educational resources.

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Screening for Cardiovascular Risk Factors and Osteoporosis Cardiovascular Disease Assessment of risk for cardiovascular disease in an asymptomatic perimenopausal or postmenopausal woman includes a detailed history and physical examination including assessment of body mass index and waist-to-hip ratios. Routine blood work should include a total fasting lipid panel and glucose. Although a baseline electrocardiogram is occasionally helpful in some circumstances, data do not support its routine use. The 2007 American Heart Association guidelines for prevention of cardiovascular disease in women support the stratification of women into optimal risk, at risk, and high risk categories (16). These categories incorporate clinical factors including medical and lifestyle issues, genetic issues (e.g., familial hypercholesterolemia) and/or Framingham global risk score. The panel identified the following groups as at risk: one major (traditional) risk factor for CVD; evidence of subclinical CAD (e.g., coronary calcification); metabolic syndrome; or poor exercise capacity on treadmill test and/or abnormal heart rate recovery post exercise. Osteoporosis Numerous organizations have published guidelines for the diagnosis of osteoporosis. There is general consensus that women aged 65 years and older should be screened for osteoporosis. Younger postmenopausal women may be offered bone density testing in the presence of additional risks, although there is variability among guidelines in terms of which factors should prompt early screening. The ideal interval for repeat testing and the age at which screening should stop are unknown. Of note, however, routine measurements should be no more frequent than every 24 months, as small differences in results may be within error range of the instrument. Several techniques are available for assessing bone density, and while these techniques vary in cost, accuracy, and radiation exposure, the choice of procedure is typically determined by local availability. Plain radiographs lack sufficient sensitivity to detect early bone loss and are not useful in screening. Results of bone density testing are expressed in standard deviations, with more negative values indicating lower bone density. The T-score compares an individual patient’s bone density with the mean peak value of a young healthy population of the same sex. The World Health Organization defines osteoporosis as a T-score (by DXA) of ≤⫺2.5 at one or more sites; a T-score of –1 to –2.49 is defined as osteopenia. The Z-score compares the patient’s bone density to that of a sex- and age-matched population; a low Z-score suggests that accelerated bone loss has occurred and should prompt a work-up for secondary causes of osteoporosis, such as endocrinopathies, malabsorption, or

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multiple myeloma. Initial evaluation for work-up of secondary causes includes measuring serum levels of calcium, alkaline phosphatase and 25-hydroxy vitamin D. Such testing may uncover a vitamin D deficiency or suggest hyperparathyroidism, which can be confirmed with a measurement of the intact parathyroid hormone level. Further investigation is guided by the clinical presentation.

Treatment for Hot Flashes Medications Moderate-to-severe hot flashes are treated most effectively with estrogen (with concurrent progesterone if the patient has a uterus). Treatment with hormone therapy should be continued for the shortest duration Hot flashes are most possible, with consideration given effectively treated with to a trial of discontinuation every hormone therapy, but many 6 to 12 months (see Chapter 16). women choose to avoid hormones Many women choose not to and may benefit from alternative take hormones, and there are several non-hormonal medications agents. available to them (Table 15-1), including continually acting medications such as SSRIs, SNRIs, alpha-adrenocepter antagonists and antidopaminergic agents. Paroxetine (Paxil), which has been shown to be the most effective SSRI (5), and venlafaxine (SNRI) are more effective than gabapentin. Paroxetine should not be used for women taking tamoxifen because paroxetine interferes with active metabolites of

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Table 15-1

Non-Hormonal Medication for Hot Flashes

Medication (Usual Dose) SSRIs Paroxetine (10-20 mg) Fluoxetine (10-30 mg) Sertraline (25-50 mg) Citalapram (10-20 mg)

Efficacy

Side Effects

++ + + +/-

Nausea, weight gain, insomnia, sexual dysfunction

SNRI Venlafaxine (37.5-75 mg)

++

Appetite loss, constipation, dry mouth, loss of libido

Anticonvulsant Gabapentin (300-900 mg)

+

Appetite loss, peripheral edema, dizziness, sedation

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tamoxifen. Studies of clonidine for hot flashes demonstrate some decrease of hot flashes, but side effects (e.g., dry mouth, dizziness, sedation) limit its use.

Behavioral Techniques Behavioral and environmental planning techniques can be beneficial and have few side effects. Most patients benefit from sleeping in a cool room, keeping a cold bottle or glass of water nearby, wearing layered clothing in lighter colors and weave, using sheets and linens that breathe, avoiding foods that trigger hot flashes (e.g., alcohol, caffeine, heavy spices), and carrying a small fan. Relaxation therapy with paced respiration has been shown to reduce hot flashes in one small study. More research is needed. Alternative Treatments A high percentage of perimenopausal women use alternative treatments including soy products, herbal therapy, vitamin E, and acupuncture. To date, meta-analyses of numerous small studies looking at soy-based supplements, soy foods, and red clover extracts suggest that they are not signifiPhytoestrogens such as cantly better than placebo for hot soy supplements are flashes (17). In addition, these sometimes used by women to phytoestrogens act like selective treat hot flashes. However, these estrogen receptor modulators agents act like SERMs and their (SERMs), with estrogen effect on safety has not yet been some tissues yet anti-estrogenic established. effect on others. Patients should be warned that these products may stimulate breast cancer growth and antagonize the anti-tumor effect of tamoxifen. Because many women, notably breast cancer survivors, turn to nutritional supplements because they have been advised not to use estrogen, they should be cautioned about the lack of information regarding the risks of phytoestrogen use. Health food stores in the United States also sell a variety of herbs for treating menopausal symptoms. In short-term studies, black cohosh, dong quai, ginseng, evening primrose oil, and wild yams have been found to be no more effective than placebo for symptom control. To date, one small study found acupuncture was effective in reducing hot flashes by 50% compared with baseline (18). Additional studies are in progress. Many women report feeling better overall with the addition of regular exercise, but it has not been shown to be effective in the reduction of hot flashes.

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Summary Overall, non-hormonal therapies offer promise as adjuncts to or replacements for hormone therapy in the treatment of vasomotor symptoms. Additional

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long-term controlled studies are needed before definitive conclusions and treatment recommendations can be made about phytoestrogens and herbal products.

Treatment for Genitourinary Problems Therapy for atrophic vaginitis is aimed at symptom management. For mild symptoms or increased sexual activity, lubricants (e.g., Astroglide and K-Y personal lubricant or jelly) and daily vaginal moisturizing agents (e.g., Replens) can be helpful (Table 15-2). For moderate-to-severe symptoms associated with menopause, topical estrogens can normalize pH, thicken the epithelium, and increase secretions resulting in resolution of symptoms. A Cochrane review (19) of topical estrogen trials showed equal efficacy for the various delivery methods in treating dryness, irritation, and dyspareunia. There is some systemic absorption of estrogen from these products that can result in

Table 15-2

Products for Atrophic Vaginitis

Product Replens

Components Polycarbophil-based bioadhesive polymer that acts a moisturizer

Astroglide and K-Y Personal Lubricant

Water-soluble lubricants Use before intercourse

Vaginal estrogens Estring*

Vagifem

Intravaginal creams (dose less accurate due to applicator)

Estradiol ring placed intravaginally; delivers low dose of estradiol to the vagina for 3 months Estradiol 25-µg tablet

Premarin (conjugated estrogen 0.625 mg/g)

Estrace (estradiol 0.1 mg/g)

Directions Use every 1-3 days

Following insertion, ring should remain in place for 3 months

Insert 1 tablet once daily for 2 weeks, then for maintenance insert 1 tablet twice weekly 0.5-2 g (1/4 to 1 applicatorful) daily for 2 weeks, then taper to lowest dose 1-2 days per week 0.5-2 g (1/8 to 1/2 applicatorful) daily for 2 weeks, then 1/2 dose for 2 weeks, then taper to lowest dose 1-2 days per week

* Care should be taken not to confuse Estring with Femring, a higher-dose estradiol-releasing vaginal ring that yields systemic levels adequate to treat vasomotor symptoms.

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breast tenderness and endometrial proliferation, but there was no difference found in side effects. For this reason, however, topical estrogen should be avoided in women with undiagnosed abnormal vaginal bleeding or estrogen dependent tumors (20). Women who are unable to use hormonal Topical (vaginal) estrogen therapy should be managed with is the treatment of choice lubricants and moisturizers. for moderate-to-severe symptoms Progesterone opposition is unnecessary when topical estrogens are of vaginal atrophy; its benefits may include improving urinary used in prescribed doses (20). Topical estrogen may also im- incontinence. prove symptoms of urinary incontinence. Other initial therapies include Kegel exercises, avoidance of caffeine and alcohol, treatment of constipation, scheduled voiding, and avoidance of excessive hydration. If these measures are not helpful, referral for intensive training in Kegel exercises, pharmacologic interventions, or referral to a urologist may be indicated (see Chapter 10).

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Treatment for Depression and Anxiety Treatment decisions for the perimenopausal/postmenopausal women should be based on history of previous psychological disorder and medications used, and knowledge of patient’s current menopausal symptoms and life stressors. As in all cases of depression and anxiety, the physician needs to rule out medication effects and medical illnesses associated with depression and anxiety, including antihypertensive medication and endocrine disorders. When treating depression and anxiety, use of SSRIs or venlafaxine can be extremely beneficial and cost-effective because of their additional potential to reduce vasomotor symptoms. Limited studies to date suggest that of the herbal products, St. John’s Wort and black cohosh are most effective for depression and anxiety during menopause. Kava may be useful for anxiety but should be used cautiously because of potential hepatotoxicity (21). Short-term cognitive or behavioral psychotherapy is also beneficial. It is extremely important to attend to any marital or family stressors as well. When sleep disturbance due to effects of menopause (from hot flashes as well as other causes) is implicated in precipitating depression, short-term hormone therapy may be helpful. If depression persists despite medication and counseling, referral to a psychiatrist is indicated.

Prevention and Treatment of Osteoporosis Although bone density correlates well with fracture risk, it cannot predict if or when a woman will fracture a bone, nor can it predict the best time to start

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treatment. Available guidelines vary in their recommendation for pharmacologic treatment thresholds. There is general consensus that pharmacologic treatment should be offered to postmenopausal women with a bone density of ≤⫺2.5 or those with a fragility fracture. Several suggest treatment at higher thresholds in the presence of specific risks (Table 15-3). No currently available therapy can completely restore skeletal integrity; the best approach to fracture prevention is to limit bone loss. All women, regardless of age, should be encouraged to adopt lifestyle habits that promote attainment and maintenance of peak bone density, including adequate calcium and vitamin D intake, weight-bearing exercise, and avoidance of tobacco and excess alcohol intake. Older women should be screened specifically for fall risk. Current recommendations for postmenopausal women are for 1500 mg of calcium and 800 IU of vitamin D daily, through some combination of diet and

Table 15-3

Screening for Osteoporosis

Bone Mineral Density Testing • Age ≥65 years • Age