老年醫學

Menopause is a universal, irreversible part of the overall aging process involving a woman reproductive system, after which she no longer menstruates. Climacteric is the general term for the time from the period of this transition to the early postmenopausal phase of a woman reproductive life cycle. Perimenopause refers to the time before menopause when vasomotor symptoms and irregular menses often commence. Menopause, by definition, begins 12 months after the final menses and is characterized by a continuation of vasomotor symptoms and by urogenital symptoms such as vaginal dryness and dyspareunia.

Epidemiology
With the increasing number of individuals who are middle aged or older, the number of women who live the majority of their lives in a hypoestrogenic state also is growing. More and more women can expect to live approximately 79 years and experience the consequences of gonadal hormone loss. However, although the time spent in menopause (now up to one third of the life cycle) has increased with the phenomenon of increasing longevity, the actual age of menopause, approximately 50-51 years, has not changed since antiquity. Women from ancient Greece experienced menopause at the same age as modern women, with the symptomatic transition to menopause usually commencing at approximately age 45.5-47.5 years (McKinlay, 1981; Cramer, 1995). Factors that lower the age of physiologic menopause are few and include smoking (Cramer, 1995), hysterectomy, and living at high altitudes.

Physiology
Menopause results from loss of ovarian sensitivity to gonadotropin stimulation, which is related directly to follicular decline and dysfunction. The oocytes in the ovaries undergo atresia throughout a woman life cycle and approximately 20-25 years after menarche both the quantity and quality of follicles undergo a critical decline. Therefore, the variable menstrual cycle length during perimenopause can be due either to anovulation or to irregular maturation of follicles. However, hormonal fluctuation may not be responsible for all irregular bleeding during this period. Therefore, pelvic pathology such as uterine fibroids; uterine polyps; endometrial hyperplasia; or endometrial cancer, which becomes more prevalent during this time, must be ruled out.
During the fifth decade of life, many women are lulled into a false sense of security, thinking that because they are so close to menopause they are no longer fertile. Although fertility declines, pregnancy still can occur, as evinced by a relatively high rate of unintended pregnancies in women aged 40-44 years. In fact, the number of unintended pregnancies in this age group has increased over the past decade, (Henshaw, 1998) which underscores the need for continued contraceptive practice in heterosexual couples.
The most common change in menstrual cyclicity that occurs during the perimenopausal period in women who have no pelvic pathology and who continue to be ovulatory is a shorter menstrual cycle length (Santoro, 1996). The follicular phase of the menstrual cycle shortens because of the decreased number of functional follicles. Because these follicles, which are stimulated by follicle-stimulating hormone (FSH) during the first part of the menstrual cycle, have declined in number, less recruitment of oocytes occurs and the follicular phase shortens as a result. However, once ovulation occurs, the luteal phase remains fairly constant, at 14 days.
Over time, as aging follicles become more resistant to gonadotropin stimulation, circulating FSH and luteinizing hormone (LH) levels increase. Elevated FSH and LH levels lead to stromal stimulation of the ovary, with a resultant increase in estrone levels and a decrease in estradiol levels. Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels (Lenton, 1991). With the commencement of menopause and a loss of functioning follicles, the most significant change in the hormonal profile is the dramatic decrease in circulating estrogen levels. Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation. With menopause comes a decrease in testosterone levels too (Smith, 1994) but this decrease is not as marked as the decline in 17-estradiol (Wells, 1999).
With cessation of ovulation, estrogen production by the aromatization of androgens in the ovarian stroma as well as production in extragonadal sites continues, unopposed by progesterone production by a corpus luteum. Therefore, women who are perimenopausal and menopausal often are exposed to unopposed estrogen for long periods of time, which can lead to endometrial hyperplasia, a precursor of endometrial cancer. Estradiol levels decrease significantly because of loss of follicular production with menopause and postmenopause, but estrone, which is aromatized from androstenedione from nonfollicular sources, still is produced and is the major source of circulating estrogen in the postmenopausal female.
Androgen-to-estrogen aromatization can occur in adipose tissue, muscle, liver, bone, bone marrow, fibroblasts, and hair roots (Smith, 1994). Because most conversion of androgens to estrogens occurs in adipose tissue, the assumption frequently is made that obese women, who have more circulating estrogen levels, should have fewer complaints of vasomotor symptoms. However, this is not always the case, and vasomotor symptoms of menopause can be as frequent and severe in heavier women as they are in thinner women.
The clinical indication that menopause has occurred is the measure of an elevated FSH level. Because the FSH level rises more than the LH level, owing to the reduced renal clearance of FSH compared with LH, obtaining an FSH level alone is not helpful. On the other hand, FSH level may not be a reliable indicator because of the wide variation of FSH and LH levels during in response to increased release of gonadotropin-releasing hormone (GnRH) by the hypothalamus and increased pituitary sensitivity to GnRH.

CLINICAL EFFECTS OF MENOPAUSE
Throughout the time when the physiologic changes in responsiveness to gonadotropins and their secretions occur, with resultant wide variation in hormonal levels, women often experience several symptoms that are collectively termed the climacteric syndrome. Typical climacteric symptoms include hot flashes or flushes, insomnia, weight gain and bloating, mood changes, irregular menses, mastodynia, and headache. As already noted, the length of time over which the climacteric occurs is widely variable, and symptoms may begin during perimenopause and continue for 5-10 years after menopause.
Since climacteric symptoms occur during menopause not because of a deficiency in estrogen but because ovarian function is irregular and estrogen levels fluctuate considerably, stopping hormone fluctuation with oral contraceptive pills (OCPs) and hormone replacement therapy (HRT) will alleviate climacteric symptoms. Ovarian function and, therefore, menstruation usually does not resume if the woman has experienced one year of amenorrhea. Cessation of menstruation in women of the appropriate age continues to be the best confirmation of loss of follicular function. As the postmenopause years progress, with an accompanying loss of ovarian response to gonadotropins, associated symptoms of the climacteric also decline.
The effects of gonadal hormone depletion can be obvious on pelvic examination, with changes noted as early as perimenopause in some women. The reproductive organs of a woman of reproductive age differ greatly in appearance from those of a woman who is menopausal. With loss of estrogen, the vaginal epithelium becomes redder owing to thinning of the epithelial layer and increased visibility of the small capillaries below the surface. Later, as the vaginal epithelium further atrophies, the surface becomes pale because of a reduced number of capillaries. A decrease in urine pH leading to a change in bacterial flora may result in pruritus and a malodorous discharge. Rugation also diminishes and the vaginal wall becomes smooth. Such changes often result in insertional dyspareunia, and for many women eventually lead to sexual abstinence if left untreated.
Inside the pelvis, the uterus becomes smaller. Fibroids, if present, become less symptomatic, sometimes shrinking to the point that they no longer can be palpated on pelvic examination. Endometriosis and adenomyosis also are alleviated with the onset of menopause, and many patients with pelvic pain finally achieve permanent pain relief.
The menopausal ovary also diminishes in size and is no longer palpable during gynecologic examination. In all women who are menopausal or older, noting a palpable ovary on pelvic examination warrants a full evaluation.
For most older women, a general loss of pelvic tone also occurs, and this may manifest as prolapse of reproductive or urinary tract organs. A complaint of vaginal or lower back pressure or bulging at the vaginal introitus is common in women with prolapse. On examination, cystocele, rectocele, and uterine prolapse are obvious as causes of these symptoms.
Atrophic cystitis, when present, can mimic a urinary tract infection. Women report symptoms of urinary frequency, urgency, and incontinence. However, women are more prone to urinary tract infection during this time because of atrophic cystitis, and urine culture should be obtained in all symptomatic women.
In addition to alterations in the pelvic organs, marked changes occur throughout the body. Skin loses elasticity, bone mineral density (BMD) declines, and dense breast tissue is replaced by adipose tissue, making mammographic evaluation easier.
At the time of menopause, the most common reason a woman presents to the clinician's office is because of symptomatic hot flushes. Flashes, or flushes, which are unpredictable in onset and sometimes occur over many years, are reported in about 75% of women who are perimenopausal or postmenopausal. Hot flashes often cause embarrassment and discomfort, as well as sleep disturbances and emotional lability, especially if they are intense and occur frequently. Vasomotor episodes usually last a few minutes. Episodes vary in frequency from every hour to every few days.
A woman who flushes to the extent that she has major sleep disturbances also may complain of cognitive or affective disorders resulting from sleep deprivation. The vasomotor flush is described as a feeling of warmth or heat that begins from the umbilical area and moves upward toward the head, followed by sweating of the head and upper body. Some other cardiovascular or neurologic symptoms, such as palpitations, dizziness, light-headedness, and vertigo, also can occur, with or without flushing, making the episode more difficult to classify simply as a climacteric symptom. Because of the wide range of symptoms, symptomatic women who have risk factors for a condition other than menopause should undergo thorough evaluation.

OSTEOPOROSIS
Although osteoporosis is one of the most pervasive conditions in older women, the condition often is not taken seriously enough by menopausal women. With proper intervention, osteopenia is a largely preventable sequela of menopause. A recently published article by Grady and Cummings (2001), a meta-analysis of 22 trials with data on a total of 8800 women, found a reduction in risk of nonvertebral fractures of 27% in older women who received HRT. For the subset of hip and wrist fractures, the risk reduction was greater, at 40%, increasing to 55% in women younger than 60 years.
With onset of menopause BMD is lost rapidly because bone resorption, uncoupled from bone formation, is accelerated, whereas formation continues at the premenopausal rate. Trabecular bone is affected more than cortical bone and bone loss therefore more commonly is seen at the vertebral, hip, and radial sites. Normal bone loss associated with senescence is different from the accelerated bone loss seen after menopause. Bone loss in just the few years after onset of menopause may be as high as 20% of the lifetime bone loss (Grady, 2001).
The overall effect of menopausal bone loss is reduction of bone strength, leading to an increased risk of fracture. The younger the patient age at cessation of ovarian function, the more severe bone loss is likely to be. Likewise, the lower the woman bone mass when entering menopause, the more severe the osteoporosis will be. Severity of osteoporosis also is related to race, being worse in Caucasians than in Asians, and least severe in women with dark complexions. Other risk factors are smoking and slender build. Osteoclasts have been shown to have estrogen receptors, and this is hypothesized to be the mechanism by which estrogen replacement protects against osteoporosis.
Bone densitometry is the most accurate clinical predictor of osteoporosis. If bone mass is less than 1 standard deviation below the average for the specific bone measured, then the individual is at a much higher risk of fracture. Other risk factors, such as low serum estrogen level, female sex, and low serum androgen level, have been shown to increase fracture risk but have not been found to have as strong an association as bone densitometry. Bone densitometry testing is recommended for all women who are postmenopausal. Neither the age of initial BMD screening nor the optimal frequency of screening has been determined.
As noted, estrogen therapy is considered the optimal therapy for osteoporosis. Oral and transdermal routes have been approved for osteoporosis prevention in women who are menopausal and considered at risk. Women who are menopausal and the elderly should be treated early and on a long-term basis, unless estrogen replacement therapy (ERT) is contraindicated.
Because loss of ovarian function is a universal occurrence and not all women can or will use HRT, other therapies have been developed. These include raloxifene, calcitonin, and bisphosphonates. Raloxifene acts directly on estrogen receptors and modulates them to decrease bone resorption, resulting in reduced vertebral fracture risk (Ettinger, 1999) and increased BMD. No effect on hip fracture risk has been documented (Ettinger, 1999).
Calcitonin is a peptide hormone that acts by inhibiting osteoclasts, which are involved in bone resorption activity. A decreased vertebral fracture rate has been demonstrated with this therapy, as has a small increase in BMD in older women. Serum calcium levels must be monitored in patients taking this drug.
Bisphosphonates are the most useful pharmacological intervention and work as antiresorptives. They have been shown to have a beneficial effect on vertebral and hip fracture rate and to effect a more significant increase in BMD than raloxifene and calcitonin (Harris, 1999; Black, 1996). Two widely used and effective bisphosphonates are alendronate and risedronate. The Vertebral Efficacy With Risedronate Therapy (VERT) study was conducted at 110 centers and included 2458 women who were postmenopausal and had vertebral fractures. Risedronate was given at a dose of 5 mg for 36 months and showed a statistically significant reduction in relative risk of new vertebral fractures (RR = 0.59, 95% confidence interval (CI) 18-58%). Cumulative incidence of nonvertebral fractures also was reduced (Harris, 1999).
Alendronate was first introduced with 10 mg daily dosing for treatment of osteoporosis. Now patients can be prescribed a weekly 70 mg dose. Supplementation to 1000-1500 mg of calcium per day remains a mainstay of prevention therapy, as does vitamin D supplementation and regular weight-bearing exercise. Excessive salt, animal protein, alcohol, and caffeine offset these benefits. Unlike estrogens, which are commonly administered for many years, often decades, the long-term use of bisphosphonates has not been fully studied and is currently under investigation.

CARDIOVASCULAR
Coronary artery disease (CAD) is well known to be increasingly prevalent with older age in both men and women. However, menopause increases the risk for women still further and independently of age. Prior to menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years. After menopause, women come to have similar risks of CAD as men of the same age. As a result, the rate of death in women from CAD is increasing. The Framingham study was pivotal in showing the relationship between menopause and increased cardiovascular mortality rate (Kannel, 1976).
The benefit of estrogen on cardiovascular mortality rate is due to many factors. One mechanism appears to be estrogen effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different, (Assman, 1998) and that triglycerides, HDL, and lipoprotein (a) Lp(a) may be more significant in women (Erikkson, 1999). Women with elevated Lp(a) should be treated more aggressively and the treatment considered should include ERT as well as a statin. A positive relationship between ERT and reduction of primary cardiovascular risk has been shown in several studies, and the reduction in risk in women who are taking ERT may be similar to the risk reduction of those receiving specific lipid-lowering therapy (Darling, 1997).
The Heart and Estrogen/Progestin Replacement (HERS) Study (Hulley, 1998; Wells, 1999; Grady, 1998), a study of 2763 women who were postmenopausal with known CAD, compared the effect of continuous combined HRT versus that of placebo over an average of 4.2 years. No beneficial reduction of CAD event rates was seen initially in the HRT groups. In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, which offset a later reduction in risk in the HRT group. An 11% reduction in LDL level and a 10% increase in HDL level were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids, and that estrogen alone is not adequate therapy for secondary prevention of CAD.
The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which included 875 healthy postmenopausal women, compared various CAD risk factors as predictors of outcomes in women who received various HRT regimens by randomizing the participants to receive placebo or 1 of 5 regimes of estrogen/progestin therapy (Writing Group for the PEPI Trial, 1995). All treatment groups showed an overall improvement in their HDL and LDL levels compared with the placebo group. The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups. However, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.
The Nurses?Health Study reported a risk reduction of approximately 40% for primary cardiovascular disease in women who were postmenopausal and using HRT compared with women who had never used HRT, irrespective of duration of use (Grodstein, 2000). The risk reduction did not appear to be dose dependent. ERT has a role in primary prevention of CAD.
The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by ERT (Abu-Halawa, 1998). Progression of early atherosclerosis in women who were postmenopausal and smoked, as measured by carotid intimal thickness, was greater over time than in women who smoked and were on ERT (Teeds, 1999).

BREAST CANCER ISSUES
ERT is known to benefit women who are postmenopausal in a multitude of ways. However, breast cancer is frequently a concern for women, as some data indicate that ERT increases its risk. Estrogen's possible link to cancer also is suggested by the fact that the risk of breast cancer is increased in women with an earlier age at menarche and later age at menopause. With early age at pregnancy however, and the interruption of menstrual hormonal changes, a reduction in risk is seen.
Data suggest a slightly increased relative risk with estrogen use at approximately 1.1-1.3 (Schairer, 2000; Collaborative Group on Hormonal Factors in Breast Cancer, 1997) but not all the evidence supports this (Gapstur, 1999). The risk appears to be related to duration of use, with longer-term users being more affected (Lando, 1999).
Data suggest that the addition of sequential progestin to the regime increases the relative risk of subsequently developing breast cancer beyond the risk with estrogen alone. However, the suggestion has been made that continuous combined HRT using much smaller doses of progestin attenuates this risk (Ross, 2000). Most earlier studies looking at breast cancer risk and ERT were conducted at a time when the progestin in HRT was cyclical.
Notably, women with a history of using HRT have more localized tumors as well as better survival rates. That is, women receiving HRT who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis (Collaborative Group on Hormonal Factors in Breast Cancer, 1997), including smaller tumor size, negative lymph node involvement, and more well-differentiated tumor histology (Colditz, 1990; Holli, 1990; Strickland, 1992; Squiteri, 1994; Bonnier, 1995; Salmon, 1995; Harding, 1996; Magnusson, 1996; Fowble, 199.
A beneficial effect on breast cancer mortality rate has been shown in women who are postmenopausal and have received HRT compared with controls who have no prior history of HRT use (Schairer, 2000). Studies do not agree on whether this is because of earlier detection or because of effects of the therapy itself on breast tissue. The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for ERT on an individual basis, with consideration of the overall balance of risks and benefits. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly.

CENTRAL NERVOUS SYSTEM EFFECTS
The association of estrogen and memory function is an intriguing area of research. Normal aging itself shows a decline in certain cognitive capabilities, and a lack of estrogen may contribute to this process. If this is the case, postmenopausal ERT may be able to preserve this function and slow or even prevent decline in certain cognitive functions. An inherent difficulty in this area of study is the limitations of objective cognitive testing for functions such as memory. In general, ERT is associated with better performance on memory testing in women who are postmenopausal than in controls who are postmenopausal and not receiving ERT (Sherwin, 1997; Resnick, 1997). The estrogen effect is one of slowing the decline of preserved memory function. Further clinical research needs to be carried out in this area to differentiate the benefits of estrogen in cognitive function in women who do and in women who do not develop clinical dementia.
Currently, data suggest that women have a higher incidence of Alzheimer disease than men do, even after allowing for the longer life span of women (Anderson, 1999), since Alzheimer disease is primarily an age-related condition. ERT appears to reduce the relative risk of developing this condition and/or delaying its onset (Tang, 1996; Kawas, 1997). Estrogen has not been demonstrated to show an improvement in cognitive function in patients with Alzheimer disease, that is, it cannot reverse previous cognitive decline, and therefore has no role as a sole treatment modality in Alzheimer disease. However, estrogen may be beneficial as adjuvant therapy in conjunction with cholinesterase inhibitors.
Perimenopause is frequently a time of depressive symptoms, associated with direct hormonal effects through variation in levels, changes in life circumstances, and secondary to effects such as estrogen-related sleep disturbance and vasomotor symptoms. However, major depression is associated with the female sex at all ages, and objective demonstration of a cluster of cases around menopause has been difficult, although anecdotally this appears to be true.
Regardless of whether the criteria for a definitive diagnosis of major depression are met, depressive symptoms always should be considered in the context of level of functioning; any impairment warrants consideration of intervention.
In all but a very few cases, distinguishing the etiology of the symptoms as menopausal versus primary depression is usually not possible. Treatment of depressive symptoms with estrogen in perimenopause, the postpartum period (Gregoire, 1996), and premenstrual syndrome is common, with observed resultant improvement in functioning and mood, both subjective and objective, in many clinical instances. Clinical depression, however, warrants treatment with antidepressants, with estrogen showing benefit as adjuvant therapy in this scenario.
The microcellular effects of estrogen in the CNS have yet to be clearly outlined but may reveal intricate processes by which estrogen has a direct effect in CNS functioning. One of these processes may turn out to be reduction in free radical damage by ERT.

MENOPAUSE MARKERS
Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. The large cyclical variation of estradiol and estrone seen during the menstrual years ceases and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium give a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells. No specific changes related to menopause have been found in thyroid function.
Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophy. No secretory changes are seen after menopause, as no ovulation occurs and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia also can be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to rule out hyperplasia and cancer of the endometrium in postmenopausal women.

REPLACEMENT THERAPY
Among the many reasons to treat symptoms of estrogen level fluctuation prior to actual menopause are to provide relief of vasomotor symptoms; reduce the risk of unwanted pregnancy; avoid the irregularity of menstrual cycles, and mitigate the long-term effects of menopause, eg, osteoporosis, cardiovascular disease, and decline in cognitive function.
The time to begin therapy depends on the patient history of present illness and past medical history. Whether a woman is in the transition or postmenopausal will help in deciding on the most suitable type of therapy. Each patient should make a choice after receiving counseling on all the facts and an explanation of the options. For example, the perimenopausal woman may be started on HRT if either she or her spouse has undergone a sterilization procedure, whereas the same woman may need an OCP if she still needs birth control. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, ethnicity and economics also play roles in the final decision, and all these must be weighed carefully by the doctor and patient together.
Adverse effects of the therapy may include bloating, mastodynia, vaginal bleeding, and headaches. Unexplained side effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.
HRT can be given either systemically through the oral, transdermal, or topical routes; or locally via the vaginal route by cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms. Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, and venous thrombosis. Well-differentiated and early endometrial cancer, once treatment for the malignancy is completed, is no longer an absolute contraindication. Estrogen receptor positive breast carcinoma traditionally has been a contraindication, but this too has been challenged recently. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens, but the other concomitant protective effects of estrogen are lost. Other lternative products ranging from herbal preparations to dietary supplements containing various phytoestrogens, reputed to smooth out the transition from perimenopause to postmenopause are available. However, these require rigorous and objective evaluation, which has yet to be carried out.