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Menopause elicits a constellation of effects on the body, including an increased incidence of cardiovascular disease and bone demineralization. These are major causes of morbidity and mortality in the aging woman. Other changes include a higher incidence of breast cancer, an increased prevalence of Alzheimer's disease and vaginal and vulvar atrophy. Options for treatment and prevention of these problems are numerous. In this review we shall discuss the medical treatments which address these problems, specifically analyzing the risks and benefits of menopausal hormone therapy (MHT) and selective estrogen receptor modulators (SERMS), raloxifene and tamoxifen.

DEFINITIONS

The menopausal transition

The menopausal transition, usually four years in duration, begins when menstrual irregularity appears. This is a result of a higher percentage of anovulatory cycles as the follicular pool from the ovary is exhausted. However, follicle-stimulating hormone (FSH) levels are not consistently elevated, and vary considerably from month to month. Estradiol levels are normal or elevated during this time and there is a much higher incidence of dysfunctional uterine bleeding for which patients will seek evaluation (1).

Menopause

Menopause is defined as the cessation of menstruation for 12 months in a woman over age 45 and occurs on average at the age of 51. This is a result of a decline in ovarian function - estrogen and progesterone are no longer being produced because the ovary has completely depleted its follicular pool. There is no relationship between a woman's age at menarche and menopause. However, a woman's age at menopause is reflective of her mother's age at menopause. Menopause is known to occur approximately one and a half years earlier in tobacco users (1).

Premature ovarian failure

Premature ovarian failure has been defined as three to six months of amenorrhea accompanied by FSH levels greater than 40 IU/L on two occasions, at least one month apart in a woman less than 40 years old. The designation of 'premature menopause' for such patients implies that menses will never happen again and this term should not be used. Premature ovarian failure or insufficiency are more neutral terms, since young women with prolonged hypergonadotropic amenorrhea, unlike their older counterparts, are far more likely to have some intermittent ovarian function after the diagnosis has been made (2).

PHYSIOLGIC CHANGES ASSOCIATED WITH AGING AND MENOPAUSE

The cardiovascular system

Lipoprotein changes

Total cholesterol increases with age, and this increase may be accelerated by menopause. It is only after menopause, around age 65, that a woman's risk of heart disease increases and equals a man's for her age (1). Low density lipoprotein (LDL) and total cholesterol increase, whereas high density lipoprotein (HDL) decreases. The decrease in desirable, cardioprotective HDL is thought to be one of the causes of increased coronary heart disease, myocardial infarction and stroke in postmenopausal women (1).

Figure 1. Causes of Mortality in Women in 2000 (3)

Despite these changes with advancing age, there are ways to prevent abnormal lipid levels from occurring. Through exercise, a low cholesterol diet, and cholesterol lowering drugs, patients with high LDL and total cholesterol levels are able to significantly lower these lipoproteins (4). Consistent with findings of the WHI and HERS trials, MHT alters biochemical markers favorably but does not improve cardiovascular disease (CVD) outcome. The Kronos Early Estrogen Prevention Study (KEEPS) is currently underway to determine if earlier intervention with lower-dose hormone therapy will ultimately improve CVD outcome.

Table 1. LIPID CHANGES WITH SERMS
Therapy	None	Estrogen (oral) (5)	Estrogen (patch)	Estrogen + Progestin (5)	Raloxifene (6)	Tamoxifen (7)
Total cholesterol
HDL					-	-
LDL
TGs			-		-	-

Coagulation

After menopause, there are changes in clotting parameters. There is an increase in fibrinogen, plasminogen activator inhibitor-1 and factor VII which cause a relative hypercoagulable state. This is thought to be another contributor in the increase in cardiovascular disease and cerebrovascular disease in older women. Estrogen therapy decreases fibrinogen and plasminogen levels (1).

The Skeletal System

Osteoporosis is one of the major health concerns after menopause. Fifty percent of women over 65 have a compression fracture (8). Maintenance of bone mass is critical in order to prevent the development of osteoporosis. Height loss, up to several inches, and postural changes including kyphosis and lordosis are also caused by vertebral fractures. Between 15% and 20% of women with hip fractures die due to the fracture or its complications (8).

After peak bone mass is attained, usually around age 30, there is a slow, steady decline during the reproductive years, approximately 0.7% per year of total bone. At menopause, there is an acceleration in the rate of bone loss - 5% trabecular and 1.5% of total bone lost per year. In the first twenty years after menopause there is a 50% reduction in trabecular bone and 30% reduction in cortical bone primarily due to the lack of estrogen (9). Estrogen is responsible for promoting osteoblast (bone-forming cell) activity. It also inhibits bone remodeling and balances osteoblast and osteoclast (bone-resorbing cell) activity. With menopause and a decrease in serum estrogen there is an increase in the rate of bone loss (10). The result of this acceleration in bone turnover is an increase in serum calcium causing a decrease in parathyroid hormone (PTH) secretion. With a lowering of PTH, calciuria increases and renal production of 1,25 dihydroxyvitamin D decreases. Vitamin D production is responsible for intestinal calcium absorption and kidney tubular reabsorption. This domino effect causes a postmenopausal woman to lose 20 to 60 mg of calcium daily (10).

Bone mineral density testing

An important and sensitive test to identify bone loss is a Dual Energy X ray Absorptimetry (DEXA) scan. Usually two sites are analyzed-- the lumbar spine and the femoral neck, occasionally the radius is also checked. Scoring systems for evaluating bone mineral density (BMD) are based on the T-score and Z-score. The T-score compares the patient's BMD to young women at peak bone mass whereas the Z-score compares the patient to women her own age. It is the T-score that is used to make a diagnosis. The World Health Organization has established the following definitions:1) normal BMD as a T-score > -1 standard deviation (SD) of the mean, 2) osteopenia as BMD between -1 and -2.5 SD and 3) osteoporosis as a T-score < -2.5 SD (11). However, BMD via DEXA scan has a precision error of 2 to 4% in the vertebrae and 3 to 6% in the hip (11). It is important not to measure BMD too frequently because this may lead to clinical intervention based solely on a measurement error.

The National Osteoporosis Foundation recommends testing BMD in: 1) all women > 65 years old, 2) postmenopausal women with fractures, 3) women considering osteoporosis therapy if BMD testing would facilitate decision making, 4) postmenopausal women < 65 years old with any risk factors for osteoporosis, and 5) women who have been taking hormone therapy for a prolonged time (11).

Avoiding bone loss

Exercise, calcium and vitamin D supplementation can help protect women from bone loss. By engaging in regular weight-bearing exercise, women lose less bone than those who are sedentary do (12). Supplementing a woman's diet with 1500 mg of calcium daily can help protect her from menopausal bone loss. Adequate vitamin D levels are also crucial for calcium homeostasis and should be supplemented in older women who do not have sunlight exposure and women over 60 years of age. (10).

Treating osteoporosis

Treatment for osteopenia and osteoporosis include weight-bearing exercise, dietary modification, increasing calcium intake to 1500 mg daily with 400 IU of vitamin D and medications. There are several different types of medications: MHT, SERMS, bisphosphonates, and calcitonin. Recombinant PTH is available and tibolone may also be available in the near future.

Markers of bone turnover can be used to assess a patient's response to therapy. Urinary calcium, deoxypyridinoline, pyridinoline, hydroxyproline and N-telopeptides can be checked after one to three months of initiating treatment (1). DEXA scans, although they are currently the best method for determining bone mass, should not be repeated too frequently (i.e., every year), since errors in interpretation of trends can occur commonly (14).

The Central Nervous System

The hypothalamic-pituitary-ovarian axis

Pathophysiologically, with the advent of menopause, the ovary is no longer responsive to stimulation by the pituitary gland. FSH gradually rises in a woman's waning reproductive years and during the menopausal transition. At menopause, FSH is sustained at tonically elevated concentrations due to a lack of negative feedback from estradiol or inhibin B from the ovary. Luteinizing hormone (LH) is also elevated > 50 IU/L (1). Serum estradiol falls and without MHT, blood levels are usually <10 pg/ml.

The CNS and vasomotor symptoms

Hot flashes occur in up to 85% of menopausal women. Approximately 25% of women continue to have hot flashes up to 5 years after menopause (1), although the average duration of hot flashes is one to two years. The exact etiology of the hot flash has not been elucidated but a resetting and narrowing of the thermoregulatory system is known to occur. Even slight fluctuations in temperature can make a woman feel too hot or cold (15). The hot flash is preceded by an LH surge (1). It is not the cause of the flash. In the past, hot flashes were thought to be related to a withdrawal of estrogen; however, there is no acute change in serum estradiol during a hot flash.. It is thought that decreased estrogen levels mqy reduce serotonin levls and thus upregulate the 5-HT2A receptor in the hypothalamus. Additional serotonin is released which causes activation of the 5-HT2a receptor which changes the set point temperature and results in hot flashes (59). There is also evidence to support that alpha-adrenergic receptors in the central nervous system are involved and alterations in norepinephrine may regulate this process (58). Moreover, postmenopausal women with prolonged, extremely low circulating estradiol do not all have hot flashes. Perhaps the fluctuations in estradiol are more important in the genesis of hot flashes. Regardless of their exact etiology, both hormone therapy and non-hormonal regimens can help to relieve these bothersome vasomotor symptoms.

Cognition

Women routinely complain of cognitive deficits around the time of menopause. Certain aspects of cognition appear to be related to changes in estrogen, but many are related to the aging process per se. While some studies have demonstrated improved short term and verbal memory in postmenopausal women taking estrogen (16, 17), others have not found such beneficial effects (18, 50a). MHT relieves sleeplessness and hot flashes which can be a confounder - women who are well rested function better than those who are sleepless.

Dementia and Alzheimer's disease

Alzheimer's disease is three times more common in women than in men. After menopause, less Alzheimer's disease has been observed in estrogen users (19) and the effect was greater with increasing duration of use (20). Women with preexisting dementia or Alzheimer's disease have been noted to have lower serum estradiol levels than women without dementia (21). When given estrogen, women with mild to moderate Alzheimer's disease had improvement in their dementia (22, 23) in some but not all clinical trials (24, 25) Estrogen is thought to help prevent Alzheimer's disease by regulating synapse formation in the hippocampus and by inducing acetycholinesterase and choline acetyltransferase, both of which are important in memory (26). Estrogen may also improve cognitive function because of protection against neuronal toxicity caused by oxidation and increasing metabolism of serum amyloid P (27). However, in the Women's Health Initiative Clinical Trial, hormone therapy was found to double the risk of Alzheimers and mild cognitive impairment, whether or not progestin was given (50a, 31).

Libido

Loss of libido is a very prevalent complaint in postmenopausal women. Causes for a drop in sexual interest may relate partly to a drop in both estrogen and testosterone as ovarian function stops. However, it is probably a more complex physiologic process. A double-blind randomized trial of postmenopausal women with decreased libido, receiving 4 months of oral estrogen and methyltestosterone showed that this treatment significantly improved libido (27a). Similarly, a group of women who had a bilateral oophorectomy were treated with oral estrogen and either placebo or transdermal testosterone in varying doses (28). In this group as well, treatment with testosterone improved sexual function. Women with primary adrenal failure have been given DHEA replacement to improve libido (29).

The Breast

After menopause and with aging, breast tissue is gradually replaced with increasing amounts of adipose tissue. This causes an age associated decrease in breast density, which makes mammography more effective in detecting breast disease. Breast cancer becomes more prevalent with advancing age for a lifetime risk of one out of eight woman (30). The importance of self breast exam, yearly clinical exam and annual mammography cannot be emphasized enough.

Risk of breast cancer with Menopausal Hormone Therapy (MHT)

Combined estrogen and progesterone treatment increases a woman's risk of developing breast cancer. The breast is a target tissue for estrogen. The Women's Health Initiative (WHI) study demonstrated an increased risk of developing invasive breast cancer after three years of MHT use, with an unadjusted hazard ratio of 1.26 over 5.2 years of average follow-up (31). This level of risk is biologically plausible, as it is similar to that seen in many observational studies, and similar to the small, incremental risk for breast cancer that is seen with later onset of menopause. The only risk factor identified in WHI patients for the development of invasive breast cancer was the duration of MHT use. Patients taking hormones for ten or more years were at greatest risk followed by patients using MHT for 5 to 10 years. Women who took MHT for less than five years had only a slight increase in risk. No correlation between risk factors--a patient's age, ethnicity, 5 year Gail model risk score, body mass index or family history-- and the development of breast cancer were noted (31). In women who had undergone hysterectomy and were randomized to conjugated equine estrogens alone, no increase in breast cancer risk was observed; a decreased risk, though not statistically significant, was observed in this group (50).

A subset of 307 women in The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was studied to examine the effect of MHT on mammograms. These women had a baseline mammogram prior to initiation of medication and a follow-up mammogram done one, two or three years later for comparison and review. There were no significant changes in the density of breast tissue for the women taking placebo. Of the group of women taking unopposed estrogen, 3.5% had an increase in breast density. Women taking estrogen with progestin therapy had the greatest increase in breast density on mammography. In the group taking estrogen with cyclic medroxyprogesterone acetate, 23.5% had an increase in breast density. Among the women taking continuous combined estrogen with medroxyprogesterone acetate therapy, 19.4% had increases in breast density. Even in the group taking estrogen with cyclic micronized progesterone, 16.4% had an increase in breast density. In conclusion, women taking MHT had increased breast density on mammography when compared to age matched women not taking hormones (32). Mammographic density is an independent risk factor for the development of breast cancer. Therefore, these authors theorized that the increase in breast density in women taking hormones may be a risk factor for breast cancer (32).

It had been widely believed that patients taking MHT who are diagnosed with breast cancer have a better prognosis than women not taking hormones even when matched for stage of disease (33). A study by Bonnier et al compared 68 patients who developed breast cancer while taking MHT and 272 patients with breast cancer without previous hormone use. These groups were matched for age, clinical stage of disease (tumor size, nodal status and metastases), histologic type, and hormone receptor status (estrogen and progesterone receptors). Following these patients over a mean of 50 months demonstrated a better prognosis on analyzing metastasis-free survival curves amongst the patients who had taken MHT (33). Women who develop breast cancer while taking MHT were also believed to have their cancers detected at a more favorable stage and to have less malignant disease. (34). In a study by Delgado and Lubian Lopez, patients taking MHT at the time of breast cancer diagnosis were compared to breast cancer patients who had not taken MHT. Each group consisted of 121 breast cancer patients. The cases and controls were well matched for breast cancer risk factors. There were no differences between the two groups in time since their last clinical breast exam, time since their last mammogram, time since menopause, age at menarche, gravity and parity, age at first live birth, previous benign breast pathology and family history of breast cancer. There were no differences in the type of histology of the breast cancers between the two groups. Significant differences were seen with respect to cancer stage at time of diagnosis. Compared to controls, MHT users had a higher rate of well-differentiated tumors and more estrogen receptor positive tumors. When taking into account the length of time a patient had taken MHT, the longer the patient took MHT the higher the likelihood that the breast cancer would be a low stage. These investigators theorize that their findings are possibly due to increased surveillance of patients taking hormones. Due to more regular evaluations, hormone users may have their breast cancers detected earlier accounting for the lower staged tumors. Another explanation is that patients who take hormones develop less aggressive tumors (34). Taken together, these data suggest that patients who develop breast cancer while using MHT have a better prognosis.

These notions were disproven by the WHI Clinical Trial. Women randomized to combined MHT with E+P had a higher risk of invasive breast cancer. Tumors in the women taking combined HT were comparable in histology and grade to the placebo group but were at a more advanced stage (31).

Assessing breast cancer risk

The Gail Model was developed to help clinicians determine if a patient was at higher risk than the general female population for the development of breast cancer (30). It takes into account the following: 1) age, 2) age at menarche, 3) age at first live birth, 4) number of first degree relatives with breast cancer, 5) number of previous breast biopsies, and 6) number of breast biopsies that were hyperplastic. This model provides an individualized risk for developing breast cancer over the next five years and over a lifetime. Other prospective scoring systems have been developed, but as of this writing there is not dominant system that has proven to be superior to others. By calculating a woman's risk of breast cancer with this model, a clinician can use the information to determine if a woman should consider chemoprophylaxis with tamoxifen to protect herself from an excess risk of breast cancer. Moreover, women with a high risk of breast cancer may wish to avoid hormone therapy, despite the lack of definitive data on how much it may increase their risk of breast cancer.

The thyroid gland

As women age, their cumulative risk of hypothyroidism increases. Frequently symptoms are ignored or misattributed to other causes, making the diagnosis difficult. It is recommended that all women, even asymptomatic females, have a thyroid stimulating hormone (TSH), level checked in their fourth decade and then every five years starting in the sixth decade (1).

The ovary

The postmenopausal ovary was previously thought to produce steroid hormones such as androstenedione and testosterone. However, there are reasons to doubt that this is the case. Couzinet et al, recently studied 18 postmenopausal women with complete adrenal insufficiency, 3 of whom were ovariectomized and compared their hormone levels to 30 postmenopausal women with normal adrenal function of which 15 were ovariectomized. All patients with adrenal insufficiency had very low levels for total testosterone, free testosterone, androstenedione and dehydroepiandrostenedione sulfate (DHEAS) whether or not they were ovariectomized. By giving dexamethasone to the women with functional adrenals, plasma androgen levels for testosterone, androstenedione and DHEAS all fell to the limits of the assay for both postmenopausal and ovariectomized patients. The same investigators provided further evidence that the postmenopausal ovary does not produce androgens by doing tissue analyses for intra-ovarian testosterone, androstenedione, 4 key steroidogenic enzymes and FSH and LH receptors in postmenopausal and premenopausal ovaries. Intraovarian androgens were very low in the postmenopausal ovaries. Steroidogenic enzymes were absent or very low and FSH and LH receptors were absent in the postmenopausal ovaries. Premenopausal control ovaries demonstrated local androgens, all 4 steroidogenic enzymes and gonadotropin receptors (45). In conclusion, the postmenopausal ovary does not appear to be able to respond to gonadotropins nor produce androgens. Androgen levels were similar in postmenopausal and ovariectomized women with intact adrenals. The postmenopausal ovary does not appear to be a biologically meaningful source of circulating steroid hormones.

The lower reproductive tract

The entire gynecologic tract as well as the urinary system contains estrogen receptors. Therefore, all of these organs can be affected by the loss of estrogen after menopause. Atrophy of the perineum, vagina and supporting ligaments of the uterus can occur. This atrophy has been believed to contribute to uterine prolapse, a diminution of vaginal lubrication and narrowing and shortening of the vagina. Coitus may become uncomfortable or even painful. However, regular intercourse can help to delay or prevent vaginal atrophy (46). Estrogen receptors in the urethra and bladder are also affected by the loss of estrogen. While MHT is effective in reversing changes associated with vaginal atrophy (47), the Women's Health Initiative Clinical Trial demonstrated a worsening of urinary incontinence in women randomized to estrogen and progesterone or estrogen alone (47a).

The adrenal gland

The adrenal gland is responsible for producing androstenedione, DHEAS and indirectly testosterone. Androstenedione levels decrease by 62% after menopause. After menopause and over the next ten years, DHEAS levels decline 74% from normal levels of premenopausal women. Testosterone, produced by peripheral conversion from androstenedione, decreases by up to 25%. Estrone is produced by peripheral conversion from androstenedione and by aromatization in adipose tissue. Therefore, estrone increases after menopause, with levels of 30-70 pg/ml. Estradiol, no longer being produced by the ovary, is produced by peripheral conversion from estrone. After menopause, estradiol falls to levels of 10-20 pg/ml. Sex hormone binding globulin (SHBG) also decreases as a result of decreasing estradiol. This may result in a higher free testosterone level and may cause mild increases in hair growth (48).

HORMONAL TREATMENT OF MENOPAUSAL SYMPTOMS AND DISEASES

Chemoprevention and therapy of breast cancer with hormonal treatment

Tamoxifen

Tamoxifen is indicated as adjuvant treatment for breast cancer. It is also prescribed for chemoprevention of breast cancer in high risk women. Because tamoxifen is a SERM, it has both estrogen-like and anti-estrogen actions. In the breast, it acts as an anti-estrogen. In the bone, on lipids and in the uterus, it acts like estrogen.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) 13,388 women were randomly assigned to tamoxifen or placebo and followed for 5 years. These women were at high risk for breast cancer because of 1) advancing age (>60 years old), 2) increased risk based on a Gail Model predicted risk of 1.66% over the next 5 years and age 35-59, or 3) a history of lobular carcinoma in situ. The objective of this study was to determine if tamoxifen 20 mg daily for five years changed these patients' risk of developing breast cancer. Secondary goals were to determine if tamoxifen had an effect on myocardial infarctions and fractures (35).

Tamoxifen dramatically reduced the risk of developing invasive breast cancer compared to placebo. The risk of breast cancer was decreased 49% in tamoxifen users. There was also a decrease in the risk of estrogen receptor positive breast cancer and nodal involvement. Fewer patients taking tamoxifen developed fractures than in the placebo group, although this was not a primary endpoint and was not statistically significant. There was no difference in the rate of myocardial infarctions between the two groups (35). In conclusion, tamoxifen decreased the risk of developing invasive breast cancer in high risk women.

Two other European studies using tamoxifen for chemoprevention did not demonstrate a decrease in the risk of developing breast cancer. The Royal Marsden Hospital Tamoxifen Chemoprevention Trial randomly assigned tamoxifen or placebo to 2494 women with a family history of breast cancer. These women were followed for 8 years. There was no difference in the rate of breast cancer between the tamoxifen and placebo groups (36). However, some of these patients were simultaneously taking HRT while enrolled in this study. Unlike the US trial, the identification of risk was based solely on family history. In the Italian Tamoxifen Prevention Study healthy women who had a hysterectomy for non-malignant reasons were studied. 5408 women were enrolled and randomly assigned to tamoxifen or placebo and compared for the development of breast cancer over five years. However, by the end of the study, only 149 patients were still being followed. These women were not at high risk for breast cancer and some of the patients were also taking hormone replacement. These investigators found no difference in the risk of breast cancer between tamoxifen and placebo groups (37). Reconciling the results of these different trials has been challenging since the populations differed and co-medications varied.

Hormonal Treatment of Osteoporosis and Osteopenia

Raloxifene

Raloxifene is a newer SERM. It is indicated for the treatment of osteoporosis. Raloxifene acts like an estrogen in its effect on bone, lipids and liver. It has anti-estrogen activities on both the uterus and the breast, making its effects more favorable than tamoxifen.

An important prospective, double blind, placebo-controlled trial examined the ability of raloxifene to prevent fractures in women with established osteoporosis in the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial (40). 7705 postmenopausal women were randomized to raloxifene, either 60 or 120 mg daily, or placebo. These women were predominately Caucasian, at low risk for heart disease, and at low risk for breast and endometrial cancer (average BMI=25 kg/m2). The objective was to determine the effect of raloxifene on the incidence of fractures. Secondary objectives included the development breast cancer, the effect on the endometrium, cardiovascular events, the incidence of venous thromboembolism and changes in cognitive function. Cardiovascular events included both cerebrovascular (stroke and transient ischemic attack) and coronary events (coronary ischemia, myocardial infarction and unstable angina).

The risk of both vertebral and non-vertebral fractures was reduced in the groups treated with raloxifene. Bone mineral density increased in both the hip and the spine in the raloxifene treated patients (38). Similar to, but even more dramatically than tamoxifen, a decrease in the incidence of breast cancer was noted in these raloxifene-treated women. Thirteen new cases of invasive breast cancer were identified in the raloxifene group compared to 27 cases in the placebo group. Again, similar to tamoxifen, raloxifene significantly reduced the risk of having estrogen receptor positive invasive breast cancer when compared to placebo (39). There was no difference between treatment groups with respect to the development of endometrial cancer - 6 cases in the raloxifene group and 4 cases in the placebo group (39).

Raloxifene and placebo did not differ with respect to cardiovascular events (40). Further investigation is underway to determine whether or not raloxifene is cardioprotective (the Raloxifene Use in the Heart Trial - RUTH). Patients taking raloxifene had a higher risk of venous thromboembolism during the three years of treatment; 49 out of 57 events occurred in this group (38). In a subset of women, cognitive function was analyzed and demonstrated no significant difference between raloxifene and placebo over three years of treatment (41).

The MORE trial demonstrated that raloxifene is effective for the treatment of osteoporosis while decreasing the incidence of breast cancer when compared to placebo. There was no difference in the risk of endometrial cancer or change in cognitive function in women taking raloxifene as compared to placebo. Raloxifene, like estrogen, is associated with an increased risk of venous thromboembolism, but it may be cardioprotective. Further investigations are currently underway to determine if there are beneficial cardiovascular effects of raloxifene in the RUTH trial.

COMPARISON OF HORMONAL TREATMENTS BY ORGAN SYSTEM

Treatment of Vasomotor Symptoms

Selective Serotonin Reuptake Inhibitors (SSRIs)

In women with hot flashes where hormone therapy is not an option, (i.e. history of breast cancer), nonhormonal prescription drugs can be used (58). Relief of vasomotor symptoms usually occurs within a week, much more rapidly than the known antidepressant effects of this class of drugs—usually 6 weeks or longer. The most common side effects of these drugs are nausea and sexual dysfunction but very low doses can be used to minimize these effects. The use of SSRIs is contraindicated in women taking MAO inhibitors.

Venlafaxine

Venlafaxine is a combined serotonin and norepinephrine reuptake inhibitor (SNRI). A randomized, double-blind, placebo controlled trial was conducted in 229 women for 4 weeks (60). Women received treatment with either placebo or varying doses of venlafaxine (37.5, 75 or 150 mg/day). There was a significant reduction in hot flashes in women receiving all doses of the mediciation and the highest dose was well tolerated. Common side effects included nausea or vomiting but when continuing therapy for another 1 to 2 weeks, the nausea resolved. Other side effects include lethargy, dizziness, constipation and sexual dysfunction (58).

Paroxetine

Paroxetine is an SSRI that can also be used to treat hot flashes. Doses of either 12.5 or 25 mg/day were studied in a randomized controlled trial of 165 women who were treated for 6 weeks. Both doses significantly reduced hot flashes when compared with placebo (62.2% and 64.6% respectively versus 37.8% (placebo)) (61). Side effects include asthenia, sweating, nausea, decreased appetite, somnolence, insomnia and dizziness (58). Paroxetine is also contraindicated in women taking thioridazine and should be used cautiously in women on warfarin (58).

Fluoxetine

Fluoxetine is another SSRI used to treat hot flashes. In addition to depression, fluoxetine has been used to treat premenstrual dysphoric disorder (PDD) (58). A randomized controlled trial evaluated 81 women who were given 20 mg of fluoxetine for 4 weeks (the same dose used to treat depression and PDD). There was a reduction in hot flashes in women treated with fluoxetine that exceeded placebo by 20% but appears less beneficial than venlafaxine (58).

Menopausal hormone therapy (MHT)

MHT has several beneficial effects. It relieves vasomotor symptoms and vaginal dryness caused by the loss of endogenous estrogen production. MHT is antiresorptive and thereby osteoprotective, and reduces incident colon cancer by almost 40% (31). MHT changes the lipoprotein profile favorably, although these latter changes do not translate into reduced cardiovascular morbidity.

However, unopposed estrogen use in women who have a uterus creates a risk for developing endometrial hyperplasia and cancer. Therefore, estrogen replacement must be accompanied by a progestin. In patients with an intact uterus who were given estrogen alone in The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial, 62% developed endometrial hyperplasia (adenomatous or atypical) over 3 years. By identifying this pathology early, patients were medically treated with high doses of progestins so that no patients developed endometrial cancer (49). It is now the standard of care to give women MHT - estrogen with a progestin – if they have a uterus.

Randomized clinical trials of hormone therapy

The Women's Health Initiative (WHI) study, started in 1993, is a clinical trial for primary disease prevention. Healthy postmenopausal women aged 50-79 were randomized to several different treatments: 1)placebo (N=8102), 2)continuous combined conjugated equine estrogen 0.625mg (CEE) with medroxyprogestone acetate 2.5mg (MPA), as Prempro® (MHT; N=8506), 3)unopposed estrogen for women who had a hysterectomy, 4) low fat diet and 5)calcium with vitamin D. Although this study was planned to continue through 2005, the MHT arm was prematurely halted on July 9, 2002 (31). Based on findings by the data and safety monitoring board, women taking MHT were determined to have an excess risk of breast cancer, meeting safety criteria to stop that arm of the trial. Few benefits of combined MHT were identified in the WHI. The study provides the largest and most definitive data that MHT decreases fracture risk. Hip and vertebral fractures were decreased by 33% and total fracture by 25% when compared to the placebo group (31). A new finding from WHI is that MHT decreases the risk of colorectal cancer by 37%. Diabetes mellitus was decreased by 7% with MHT use. Intermediate cardiovascular endpoints - lipids and blood pressure-- were similar to findings from other studies. Women had no difference in their risk of developing endometrial cancer if taking MHT or placebo (31).

The adverse events demonstrated in patients taking MHT outweighed these benefits. There was a 26% increase (8 more cases/10,000 women years) of invasive breast cancer (31). Excess risk began after 3 years of combined MHT use. A 29% increase (7 more cases/ 10,000 person years) in coronary heart disease events in HRT users was noted (31). There was a 41% increase in strokes and 200% increase in venous thromboembolic events (31). The global index, a summary of the risks and benefits of treatment, increased 15% in MHT users. However, there was no difference in total mortality or cause of death during the follow-up to date (31).

The women taking unopposed estrogen were continued on treatment beyond the initial termination of the E+P arm of the WHI. The E alone arm was halted in February 2004, approximately 6 to 8 months prior to its expected termination date. Estimated hazard ratios, over 6.8 years of follow-up, for unopposed estrogen vs placebo were: cardiovascular disease 1.12; breast cancer 0.77; stroke 1.39; PE 1.34; colorectal cancer 1.08 and hip fracture 0.61 (50). The results of this study were similar to the combined CEE and MPA arm in terms of heart disease, stroke and thromboemolic events. A striking, but not statistically significant decrease in incident breast cancer was observed (50). This same group of women, taking unopposed estrogen, were analyzed for risk of dementia and mild cognitive impairment. A hazard ratio of 1.77 for dementia was found in this group and when pooled with the CEE and MPA data the hazard for dementia was 2.19 (after excluding subjects with baseline abnormal scores on the Modified Mini-Mental Status Exam (50a)). These findings suggest that estrogen therapy alone or in combination with progestin treatment, increases the risk for both dementia and mild cognitive impairment.

Recommendations for MHT prescribing should be based upon the randomized, clinical trial results of the WHI, as they currently constitute the best available medical evidence. First and foremost, a woman should consult her physician to discuss her risks, benefits and alternatives to hormone use. Although WHI studied the Prempro® formulation only, it is biologically plausible that other systemic formulations (e.g. OrthoPrefest®), including the transdermal patch, will carry similar risks and benefits. Transdermal estrogen avoids to some extent the "first pass effect" increasing clotting factors and other estrogen sensitive proteins made in the liver, further information is necessary to conclude this definitively. It should not be assumed that switching MHT formulations protects a patient from adverse events. Women with vasomotor symptoms may consider short-term MHT use at the lowest effective dose (51). Asymptomatic women should be encouraged to discontinue MHT. Although no additional breast cancers were diagnosed in the first 4 years of hormone use, it is unknown when MHT users' excess risk begins. Until more information becomes available, it is unclear what constitutes truly "safe" short-term use (51). Another alternative is to take systemic estrogen with local progesterone applied to the uterus (52). In other words, placing a progestin-releasing intrauterine device (e.g. Mirena®) to protect the patient's uterus from the harmful effects of unopposed estrogen. Finally, women who desire long-term MHT use for quality of life reasons (after appropriate counseling) should be evaluated regularly and their decision to continue MHT periodically reassessed (51).

Unfortunately and surprisingly, given the large body of in vitro and animal data supporting a role for MHT in cardiovascular health, primary prevention of cardiovascular disease with MHT is not an effective strategy for unselected postmenopausal women. It has been speculated that subgroups of women at excess risk account for the increased overall morbidity in the WHI; however, at present, such subgroups have not been identified and the results should be applied to the postmenopausal population in general until and unless it has been demonstrated otherwise. These preliminary results can be used to more appropriately advise patients about their risks of taking MHT. Hormone therapy is no longer recommended for primary prevention of osteoporosis or cardiovascular disease. Based on the findings from WHI, MHT should not be initiated for primary prevention of colorectal cancer or Alzheimer's disease because the risks outweigh any potential benefits. Whether early initiation of MHT, within the immediate peri- or postmenopausal window, would have a more beneficial effect upon the long term outcomes of cardiovascular disease and cognitive impairment or dementia is currently a topic of research.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial assessed 875 healthy postmenopausal women over 3 years. Women were randomly assigned to the following treatments: 1) placebo, 2) conjugated equine estrogen 0.625mg, 3) conjugated equine estrogen 0.625mg with medroxyprogesterone acetate 10mg added for the last 12 days of the month, 4) conjugated equine estrogen 0.625mg with medroxyprogesterone acetate 2.5mg daily and 5) conjugated equine estrogen 0.625mg with micronized progesterone 200 mg for the last 12 days of the month. The investigators examined intermediate endpoints for cardiovascular disease, such as HDL cholesterol, systolic blood pressure, serum insulin and fibrinogen. A secondary endpoint was the effect of the various hormone preparations on the endometrium.

The PEPI Trial demonstrated an increase in HDL cholesterol in all of the treatment groups compared to placebo, with the largest increases in patients taking unopposed estrogen. LDL cholesterol levels were lower in all treatment groups compared to placebo. However, all treatment groups had higher TG levels than placebo. Fibrinogen levels were lower in the treatment groups compared to placebo (5). Unopposed estrogen use resulted in an increased risk of endometrial hyperplasia (34%), compared to the other treatment groups with a 1% risk (5). Unopposed estrogen resulted in a high rate of endometrial hyperplasia making it necessary to add a progestin (48). PEPI was not designed to evaluate clinical outcomes such as the development of cardiovascular disease.

Hormone therapy for secondary prevention of coronary heart disease was evaluated in The Heart and Estrogen/Progestin Replacement Study (HERS). This trial included 2763 postmenopausal women with pre-existing coronary heart disease and followed them over 4 years. The objective of this study was to see if initiating MHT would alter a woman's risk of future coronary heart disease events. All participants were postmenopausal, younger than 80 with a uterus and established coronary heart disease. Women were prescribed conjugated equine estrogens 0.625 mg with medroxyprogesterone acetate 2.5mg daily or placebo. The primary outcome was the occurrence of fatal or nonfatal myocardial infarction. Secondary outcomes were other cardiovascular events: coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack and peripheral arterial disease. The results showed no significant differences in the primary outcome between the two groups: 172 women in the hormone group and 176 women in the placebo group died from myocardial infarction or coronary heart disease. However, in the first year of the study, there were significantly more coronary heart disease events in the hormone group. There were no differences in other cardiovascular outcomes - 88 women in the hormone group and 101 in the placebo group. The hormone group had a higher incidence of thromboembolic events (both deep venous thrombosis and pulmonary embolus) and gallbladder disease when compared to placebo. The incidence of diabetes mellitus decreased by 3.5% over 4 years. Similar to the results of the PEPI Study on intermediate cardiovascular markers, the hormone group had a decrease in LDL cholesterol and an increase in HDL cholesterol when compared to placebo. These investigators concluded that menopausal hormone therapy did not reduce the risk of future cardiac events in postmenopausal women with established coronary heart disease. In addition, because of the increased incidence of adverse cardiac events in the first year of treatment, initiating hormone therapy in women with established coronary heart disease is not currently recommended (53). Based on the findings of the HERS Study, MHT should not be initiated for secondary prevention of cardiovascular disease.

Treatment of Vaginal Symptoms

MHT is effective in the treatment of vaginal atrophy and dryness (47). For this purpose, systemic or vaginal estrogen can be used. Locally applied estrogen can be administered in very low doses, which are believed to be safe for the uterus, even without concomitant use of a progestin. The data are currently insufficient to define the minimum effective dose, but vaginal rings, creams, and tablets have all been tested and demonstrated to reduce vaginal symptoms (63-65). Urinary incontinence, however, is not relieved by MHT and may actually be made worse; it is therefore not currently recommended to prescribe MHT for the purpose of improving urinary incontinence (47a).

MHT regimens: continuous combined and cyclic regimens

There are many ways to prescribe hormones. They are administered systemically as oral tablets or patches. Considering the importance of including a progestin, there are several different modalities of incorporating this hormone. This includes continuous combined and cyclical administrations. The continuous combined formulation means taking both the estrogen and progestin hormones in the same dose every day. Cyclical administration means that hormones are given in a cycle. First, unopposed estrogen is given followed by estrogen with a progestin. The cyclic regimen can be a cycle of every 3 days (e.g. Ortho Prefest), every 14 days (e.g. Premphase), or at the discretion of the prescribing physician (e.g. every 3 months). Although generally believed to be safe, if progestins are given less frequently than monthly, the potential for hyperplasia exists and endometrial monitoring should be considered (62).

Figure 2. FLOW CHART CYCLIC V. CONTINUOUS COMBINED REGIMENS

Cyclical administration is usually the simplest choice for women who are just entering menopause. Patients can easily make the transition from taking a low dose oral contraceptive tablet in the menopausal transition (frequently prescribed to control the irregular vaginal bleeding during that time) to this form of hormone therapy. In the beginning of starting this hormonal regimen most women will get a withdrawal bleed at the end of the treatment month. Gradually, as the endometrium thins and becomes atrophic, some women will become amenorrheic on this regimen. However, many women will continue to have a withdrawal flow despite prolonged therapy. Erratic vaginal bleeding is uncommon, however, and should be investigated. Another advantage of this method is that women know when to expect bleeding - at the end of the pill pack. If a woman becomes amenorrheic on this formulation, she should have no problems with the continuous combined therapy also.

Advantages of giving continuous combined therapy is that a lower dose of progestin can be used and patients should not expect a withdrawal flow at the end of the treatment month. Eventually, most women become amenorrheic. However, continuous combined therapy has been shown by the WHI to increase the risk of breast cancer, thromboembolic events and Alzheimer's disease. Some women also develop irregular and inconvenient vaginal spotting or bleeding. This most frequently occurs in women who have recently entered menopause and still have an endometrial lining.

Estrogen can also be administered through a vaginal ring that delivers either 0.05 or 0.1 mg/day of estradiol acetate over a three month period. This is the only vaginal estrogen that can effectively treat hot flashes (58). It may also be given transdermally as 17β-estradiol with norethinadrone acetate or levonorgestrel. Proesterone can be administered through a levonorgesttrel-releasing IUD which can be left in place for 10 years. Vaginal preparations of progesterone are also available. Applying the 4% preparation twice weekly protects the endometrium. There is no long term data about giving progesterone cream vaginally in a cyclic fashion (1).

CONCLUSION

We have reviewed the major health issues faced by the postmenopausal patient. Heart disease becomes more prevalent with the loss of estrogen and the decrease in HDL cholesterol levels that occurs concurrent with menopause. Reduced vascular compliance and subendothelial coronary plaque development accelerates after menopause and leads to increased coronary risk. This is the major cause of morbidity in postmenopausal women. Osteoporosis is another serious potential problem that faces the aging woman and can be prevented by careful screening and early treatment. There are also changes in the brain with aging. Cognition decreases and Alzheimer's disease becomes more prevalent, making it more difficult for aging women to maintain an independent lifestyle. These changes in the central nervous system and their relationship to hormones are incompletely understood. Breast cancer also becomes more prevalent with advancing age. The increased risk of breast cancer needs to be considered when choosing a treatment plan for a patient.

There are a variety of treatments available to protect women from developing problems. First and foremost, a healthy lifestyle is the best preventive medicine. Estrogen therapy will control a patient's vasomotor symptoms, prevent bone loss, maintain a favorable lipoprotein profile and prevent urogenital atrophy. Other benefits of MHT include prevention of colon cancer. The SERM, raloxifene, also can be used to treat the aging female. The advantage of a SERM compared to MHT is the lack of endometrial stimulation and a probable reduction in the risk of breast cancer. The prevention of bone loss and the beneficial effects on lipoprotein levels with SERMs are similar to those seen on MHT.

The role of hormone therapy is changing as its potential benefits and risks become clarified. Vasomotor symptoms are best relieved by estrogen and frequently cause patients to seek evaluation. However, the clinician needs to take into account all of a patient's risk factors, her medical and family history in order to determine which form of treatment is best. The ability to modulate estrogen action via the development of SERMS provides the hope that a 'perfect' SERM can be produced, which will relieve vasomotor symptoms, protect the bone and the heart, maintain a favorable lipoprotein profile and be anti-estrogenic to the endometrium and the breast. Until then, good clinical judgment and an individualized approach to assess risks and benefits for our patients using the currently available medical evidence remains the most appropriate approach.