Chapter 17 – The Postmenopausal Woman

Updated 1 April 2010

INTRODUCTION

Menopause is associated with a constellation of physical changes.  Some of these changes are directly attributable to the loss of estrogen, including hot flashes, bone demineralization and vaginal dryness. Though a matter of controversy, an increased incidence of cardiovascular disease and dementia seem to be associated with both menopause and aging.  Furthermore, other conditions, such as breast cancer, are associated primarily with aging but certainly are impacted by ovarian hormones. 
This review will address the menopausal transition, its common symptoms, and the risks and benefits of menopausal hormone therapy (MHT), specifically, estrogen replacement, the selective estrogen receptor modulators (SERMs): raloxifene and tamoxifen and other non-hormonal therapies.

DEFINITIONS

The Menopausal Transition

In 2001, The Stages of Reproductive Aging Workshop (STRAW) staging system was developed to describe various stages of the menopausal transition (Table 1). On average, the menopausal transition lasts 4 years in duration and is divided into early and late phases (1). It begins when menstrual irregularity first appears, classically defined as either a "skipped" period or by an increase in variability of cycle length by more than 7 days. It is well established that the greatest number of follicles are present in utero in the fetus at 20 weeks of gestation. These follicles undergo atresia, with a more rapid rate of decline after the 3rd decade of life (2).  The menstrual irregularity that characterize the menopausal transition occurs as this overall follicular complement decreases, which in turn leads to a decrease in the number of ovarian follicles available to grow and potentially ovulate in any given cycle.  The result is a decrease in inhibin B production. This reduction in inhibin B leads to an increase in follicle-stimulating hormone (FSH) secretion.  Early in the transition period, FSH levels are not consistently elevated, and may often vary considerably from month to month as the growing follicle cohort itself varies month to month.  The follicular phase becomes notably shorter, and as a result, estradiol (E2) production is variable and even elevated at times.  Anovulatory cycles become more prevelant, and luteal progesterone production declines.  This early phase of the transition is associated with an increase in menopausal symptoms such as hot flashes, though initially, the increase may be relatively small as there may not necessarily be a reduction in the amount of circulating E2.  By the late transition, prolonged amenorrhea (defined as > 60 days) occurs, and is associated with a persistently reduced follicle pool and failure of folliculogenesis.  At this point in the transition, estrogen deficiency begins to dominate, bone mineral density loss begins and menopausal symptoms including hot flashes and vaginal dryness will increase dramatically.    

(Table 1: The Stages of Reproductive Aging Workshop (STRAW) staging system, Fertility and Sterility 76:874-878, 2001)

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 (3). This event represents permanent failure of ovarian function secondary to depletion of the follicular pool. As such, supporting granulosa cells cease to produce estrogen and theca cells cease to produce androgens, and subsequently, estrogen and progesterone production stops. There is no established relationship between a woman's age at menarche and her age at menopause. However, it is well established that a woman's age at menopause is reflective of her mother's age at menopause (4). Although no specific linked genes have been identified, there certainly is an heritability for age of menopause, and thus, several genes are likely involved in aging (5). Furthermore, menopause is known to occur approximately 1.5 years earlier in tobacco users (6).

Premature ovarian failure

Premature ovarian failure (POF) has been defined as 3-6 months of amenorrhea accompanied by FSH levels greater than 40 IU/L on two separate occasions, at least one month apart in a woman less than 40 years old. POF is diagnosed in 5-10% of women who are evaluated for amenorrhea and the overall prevalence in the general population is thought to be around 0.5% (7). The designation of "premature menopause" for such patients implies that menses will never happen again and this term should not be used. Rather, many recommend the use of the term "premature ovarian insufficiency (POI)" to describe the syndrome. POF and POI are more neutral terms, as 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.
The treatment for POF usually consists of estrogen replacement. It is important to recognize that the risk to benefit equation of menopausal hormone therapy (MHT) for women under age 40 who have ovarian failure differs from those menopausal women aged 50-79 (8).  A preventive benefit for MHT appears to be more likely in younger women, primarily because their risks of adverse events are low.

PHYSIOLOGIC CHANGES ASSOCIATED WITH AGING AND MENOPAUSE

Cardiovascular system

 The largest health threat to women over aged 50 is cardiovascular disease (Table 2) (9). In women age 45-49, the incidence of cardiovascular disease is 3 times lower than men of matched age. However, data from the Framingham study have shown that by age 75-79, a woman's risk of heart disease increases and equals a man's risk for her age (10). Women are less likely to be diagnosed correctly, less likely to undergo the correct revascularization procedure, and less likely to survive a major cardiac event than are men.  It is critical to develop new ways to identify preclinical disease amendable to intervention and prevention. MHT for the secondary prevention of coronary heart disease (CHD) was evaluated in The Heart and Estrogen/Progestin Replacement study (HERS). This trial included 2763 post-menopausal women with pre-existing CHD and followed over 4 years. The objective of this study was to see if initiating MHT would alter a woman's risk of future events. All participants were post-menopausal, younger than age 80 with a uterus and established CHD. Women were prescribed conjugated equine estrogen (CEE) 0.625 mg with medroxyprgesterone acetate (MPA) 2.5mg daily or placebo. The primary outcome was the occurrence of fatal or nonfatal myocardial infarction (MI). 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 occurrence of fatal or nonfatal myocardial infarctions. However, in the first year of the study, there were significantly more CHD events in the MHT group; a higher incidence of thromboembolic events (both deep venous thrombosis (DVT) 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 MHT group had a decrease in LDL cholesterol and an increase in HDL cholesterol when compared to placebo. These investigators concluded that MHT did not reduce the risk of future cardiac events in post-menopausal women with established CHD. In addition, because of the increased incidence of adverse cardiac events in the first year of treatment, initiating MHT in women with established CHD is not recommended. Based on the findings of the HERS Study, MHT should not be initiated for secondary prevention of cardiovascular disease (11).

Table 2: Deaths in Women: all ages, National Center for Health Statistics, Center for Disease Control)

Lipoprotein Changes

As cardiovascular disease becomes more prevalent in the later years following menopause, a finding thought to contribute to this increased risk is dyslipidemia in post-menopausal women. In women, total and low density lipoprotein (LDL) cholesterol increase with age, and this increase is accelerated by menopause7, whereas cardioprotective high density lipoprotein (HDL) decreases. These changes lead to increased rates of coronary heart disease, myocardial infarction and stroke in post-menopausal women (12).
Despite these lipoprotein changes noted with advancing age in women, there are ways to prevent dyslipidemia. Through exercise, a low-fat diet, and cholesterol lowering drugs, patients with high total and LDL cholesterol levels are able to significantly lower these lipoprotein levels and their subsequent risk for heart disease (13). MHT increases HDL and reduces LDL, but these favorable changes do not translate into decrease cardiovascular events. Thus, improved lipid profiles in menopausal women taking MHT appear to have limited clinical significance. 
Dyslipidemia is a risk factor for atherosclerotic cardiovascular disease. Measurement of the carotid intimal medial thickness (IMT) has increasingly been used as a biologically meaningful intermediary marker of the extent and/or progression of atherosclerotic disease. As the carotid artery is an elastic artery, the muscular media is relatively small. Hence, thickening of the carotid arterial wall is essentially due to intimal thickening. Many studies have documented the relationship between the carotid IMT and the presence and severity of atherosclerosis. In 2003, the European Society of Hypertension-European Society of Cardiology recommended the use of carotid IMT measurements in high-risk patients to help identify those with atherosclerosis (14).
Another risk factor associated with atherosclerotic cardiovascular disease is the presence of arterial calcified plaques. These plaques result from the deposit and build up of calcium. Their presence in coronary arteries can predict the risk of future poor cardiovascular outcomes as it is well established that the presence of these calcifications are an early sign of coronary heart disease. A coronary artery calcium (CAC) scan using computed tomography (CT) looks for the presence of calcium calcifications in the walls of the coronary arteries. These images may supply predictive information for poor cardiovascular outcomes.

Lipoprotein Changes and MHT

The Womens Health Initiative (WHI) trials describes a group of randomized, placebo controlled, clinical primary prevention trials that were designed to test the effects of MHT, diet modification, and calcium and vitamin D supplements on cardiovascular disease, fracture risk, and breast and colorectal cancer. The WHI had three overlapping clinical trials.  One was to test the effects of a low fat diet on breast cancer and cardiovascular disease outcomes; one was to test the effect of calcium plus vitamin D on fracture outcomes, and one was to test the effects of hormone therapy in cardiovascular disease outcomes.  The hormone therapy trial consisted of three study arms: the Estrogen + Progestin arm (conjugated equine estrogen (CEE) + medroxyprogesterone acetate (MPA) was administered to women with a uterus, the estrogen-alone arm (CEE) was administrated to women without a uterus, and a placebo arm involved both women with or without a uterus. The WHI findings suggest that administration of MHT does not protect the heart and may even increase the risk of CHD. In the final analyses, CEE + MPA use was associated with a 24% overall increase in the risk of CHD (6 more heart attacks annually per 10,000 women using CEE + MPA) and an 81% increased risk of CHD in the first year alone after starting therapy. Women who had higher baseline LDL cholesterol levels at the beginning of the study were at particularly high risk of CHD with use (15).
The estrogen alone arm (CEE) differed from the CEE + MPA study in that it enrolled women who did not have a uterus, and who therefore did not need progestin. In this trial, 10,739 women with a prior hysterectomy, aged 50-79 years, were assigned to CEE 0.625 mg daily or to placebo. The study was stopped ahead of schedule in February 2004 by the National Institutes of Health because of an increased stroke risk and a lack of cardiovascular benefit. During 7.1 years of follow up, estrogen provided no overall protection against heart attack or CAD in healthy post-menopausal women most of whom were more than 10 years past menopause when they entered the study. In women 50-59 years of age at study entry, there was a suggestion of lower rates of heart attacks or procedures to revascularize thrombosed coronary arteries; however, these findings could be due to chance (16). It was noted that the WHI trials had an older age distribution and a later start of MHT initiation than is typical in clinical practice. As such, many of the women in the WHI had been post-menopausal and without estrogen for 10-12 years before randomization to HT or placebo. A multi-centered randomized trial, known as the Kronos Early Estrogen Prevention Study (KEEPS) is currently underway to determine if intervention with low-dose MHT in the years immediately subsequent to menopause will ultimately improve cardiovascular disease outcomes for women (17).
    Data from the WHI estrogen-alone arm (CEE) supports the notion that coronary calcium accrual is prevented by early intervention with estrogen.  The WHI evaluated the presence of CAC burden to determine whether or not it differed based on treatment assignment. The WHI Coronary-Artery Calcium Study (WHI-CACS) evaluated 1,064 women aged 50 to 59 years after a mean of 7.4 years.  CAC was evaluated by cardiac CT scans, which were performed blindly on patients to measure the CAC in these estrogen-alone participants. CAC scores were lower in women in the (CEE) alone group compared to those in the placebo group. The mean CAC score was 83.1 for (CEE) and 123.1 for placebo. After taking into account other heart disease risk factors, the risk of having mild-to-moderate CAC was 20-30% lower and the risk of severe CAC was 40% lower in the (CEE) group compared to placebo. After the trial ended, the calcium plaque build-up in the coronary arteries was lower in women randomized to estrogen compared to placebo (18).
In conclusion, these studies show that most women have minimal CAC and minimal increases in carotid IMT prior to menopause. Furthermore, these findings imply that ovarian hormones exert a protective effect on the cardiovascular system in premenopausal women, even though they do not appear to maintain a protective role after menopause. Despite these encouraging findings suggestive that early intervention with hormones may delay the onset of clinical heart disease, prescribing hormones for this purpose cannot be recommended unless definitive data become available that demonstrate that the significant risks of hormones are outweighed by any benefit, should it exist.

Coagulation

After menopause, there are noted changes in clotting parameters. There is an increase in procoagulation factors including fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and factor VII, all of which cause a relatively hypercoagulable state. These increases are thought to be another contributor to the increase in cardiovascular and cerebrovascular disease in older women. With the administration of oral estrogen therapy, most of these procoagulation parameters improve, as evidenced by a decrease in fibrinogen and plasminogen levels; however, these decreased coagulation factors are associated with an increase in venous thromboembolism (VTE) (19).  MHT in currently used doses is associated with an approximately 3-fold increase in VTE events.  Transdermal estrogen preparations may offer an advantage, and in one non-randomized study, were not associated with an increased risk of VTE (20). Tamoxifen increases VTE risk in a manner similar to oral estrogen, whereas raloxifene is associated with fewer VTE events than tamoxifen or estrogen (21-22).  

Skeletal System

Osteoporosis is a major concern for postmenopausal women, leading to substantial morbidity and mortality.  Fifty percent of women over age 65 have a compression fracture. Maintenance of bone mass is critical 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. The mortality rate of women with hip fractures is 15% and 20% within the year following the fracture (23)
After peak bone mass is attained, usually around age 30, there is a slow, steady decline during the reproductive years, when approximately 0.7% of total bone is lost per year. At menopause, there is an accelerated rate of bone loss; 5% trabecular and 1.5% of total bone is lost per year. In the first 20 years after menopause, there is a 50% reduction in trabecular bone and 30% reduction in cortical bone, primarily due to the lack of estrogen (24).
Bone mass is affected by sex steroids. Estrogen is responsible for promoting osteoblast (bone-forming cell) activity. It also inhibits bone remodeling and balances osteoblast and osteoclast (bone-resorbing cell) activity. As levels of serum estrogen decline in menopause, there is an increase in the rate of bone loss (25). As such, increased bone turnover increases serum calcium.  This increase in serum calcium, in turn, causes a decrease in parathyroid hormone (PTH) secretion, followed by calciuria and decreased renal production of 1,25 dihydroxy-vitamin D. Vitamin D 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 (26-27).

Osteoporosis Screening

There are few agents that successfully increase bone mineral density (BMD) once it has been lost.  It is a challenging public health problem to provide a cost-effective approach to identify women who are most likely to fracture, and to preferentially target them for screening and therapy.
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 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 (WHO) has established the following definitions:

• normal BMD as a T-score > -1 standard deviation (SD) of the mean
• osteopenia as BMD between -1 and -2.5 SD
• osteoporosis as a T-score < -2.5 SD

However, BMD via DEXA scan has a precision error of 2 to 4% in the vertebrae and 3 to 6% in the hip (28).
Bone density screening is useful, but does not provide sufficient information about true fracture risk.  Recently, the World Health Organization (WHO) has developed the Fracture Risk Assessment Tool (FRAX), to identify those women who are at the greatest risk for fracture.  FRAX was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm or humerus fracture) taking into account femoral neck BMD and the risk factors listed below in (Table 3). Clinicians can use the FRAX tool to make clinical decisions regarding BMD (http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9).
The National Osteoporosis Foundation (29) recommends testing BMD in:

• women > age 65 years
• post-menopausal women age 50-69 years with an increased risk profile (see table 2)
• women > age 50 years with a fracture
• women with a medical condition (eg. Rheumatoid Arthritis) or taking a medication (e.g., glucocorticoid > 5 mg daily dose prednisone or equivalent for > 3 months) that will pre-dispose to low BMD
• women being considered for pharmacological therapy for osteoporosis
• women being treated for osteoporosis, to monitor their progress
• post-menopausal women discontinuing estrogen therapy

Other considerations for BMD testing include:

" Estrogen deficient women of any age at clinical risk for osteoporosis
" Individuals with vertebral abnormalities
" Individuals with primary hyperparathyroidism

 

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 (30). Supplementing a woman's diet with at least 1200 mg of calcium daily can help protect her from menopausal bone loss. Adequate vitamin D levels are also crucial for calcium homeostasis.  Cholecalciferol (vitamin D3) 1000 IU or more should be taken daily to assure adequate vitamin D stores.  This is particularly important for women who do not have sufficient sunlight exposure (at least 15 minutes per day to non-sunscreened skin) and women over 60 years of age (31).

Table 3 WHO Technical Report: Fracture Risk Assessment Model

Risk Factors Included in the Fracture Risk Assessment (FRAX) Model

" Current age

" Rheumatoid arthritis

" Gender

" Secondary osteoporosis

" A prior osteoporotic fracture

" Parental history of hip fracture

" Femoral neck BMD

" Current smoking

" Low body mass index (kg/m2)

" Alcohol intake (3 or more drinks/day)

" Oral glucocorticoids ≥5 mg/d of prednisone for ≥ 3 month

Treating osteoporosis

Treatment for osteopenia and osteoporosis includes weight-bearing exercise, dietary modification, increasing calcium intake to at least 1200 mg daily with vitamin D supplementation and the introduction of other medications. There are several different types of medications that can be used to treat low BMD: bisphosphonates, raloxifene, calcitonin and MHT are all clinically proven anti-resorptives (Table 4). In addition, recombinant PTH can lead to accrual of new bone.

    
Raloxifene is classified as a SERM and it is indicated for the treatment of osteoporosis. It acts like a pro-estrogen in its effect on bone, lipids and liver and acts as an anti-estrogen on both the uterus and the breast. This makes its effects more favorable than tamoxifen, which acts like a pro-estrogen on the uterus.
The landmark MORE (Multiple Outcomes of Raloxifene Evaluation) trial evaluated the ability of raloxifene to prevent fractures in women with established osteoporosis. 7705 post-menopausal women were randomized to either 60 or 120 mg of raloxifene versus placebo. The risk of both vertebral and non-vertebral fractures was reduced in the groups treated with raloxifene, and BMD increased in both the hip and the spine in the raloxifene treated patients (32). Furthermore, a decrease in the incidence of breast cancer was noted in the raloxifene treated women, and the risk of having estrogen receptor positive invasive breast cancer was decreased when compared to placebo (33). There was no difference between treatment groups with respect to the development of endometrial cancer.
Once a patient has been started on therapy, markers of bone turnover can be used to assess a patient's response. Urinary calcium, deoxypyridinoline, pyridinoline, hydroxyproline and N-telopeptides can be checked after 1-3 months of initiating treatment (34). DEXA scans, although they are currently the best method for determining BMD, should not be repeated too frequently, such as yearly, since errors in interpretation of trends can occur commonly (35). It is recommended that DEXA scans be repeated no more than every 2 years.

Central Nervous System

Vasomotor symptoms and "hot flashes" adversely affect the quality of life and functional status of most women during the menopausal transition. Hot flashes can occur in up to 85% of menopausal women. Although the average duration of hot flashes is 1-2 years, approximately 25% of women continue to have hot flashes up to 5 or more years after menopause. Politi et al. estimated the duration of vasomotor symptoms in a longitudinal study on 438 women in the cohort of the population-based Melbourne Women's Midlife Health Project. The onset and cessation of vasomotor symptoms were reported, and stratified according to whether or not MHT was used. They found that the mean (SD) duration of bothersome menopausal symptoms for women who never used MHT was estimated to be 5.2 (3.8) years (36).
The exact etiology of the hot flash has not been elucidated but a resetting and narrowing of the thermoregulatory system is believed to occur. 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. Others have related hot flashes to variability in both estradiol and FSH.  It is thought that decreased estrogen levels may reduce serotonin levels and thus upregulate the 5-HT2A receptor in the hypothalamus. As such, additional serotonin is then released which can cause activation of the 5-HT2a receptor itself. This activation changes the set point temperature and results in hot flashes (37). Regardless of the exact etiology behind the hot flash, both hormone therapy and non-hormonal regimens can help to relieve vasomotor symptoms.

Cognition

Women routinely complain of cognitive deficits around the time of menopause. Certain aspects of cognition appear to be related to the decline in estrogen, but many are related just to the aging process itself. While some studies have demonstrated improved short term and verbal memory in postmenopausal women taking estrogen (38-39), others have not found such beneficial effects (40-41). Interestingly, a study by Greendale et. al of 2,362 participants longitudinally across 4 years from the Study of Women's Health Across the Nation (SWAN) determined the effects of the menopausal transition and MHT use on cognitive performance in midlife women. The outcomes analyzed were longitudinal performance in 3 separate areas: processing speed, verbal memory and working memory. The results of the study showed that, consistent with transitioning women's perceived memory difficulties, perimenopause was associated with a decrement in cognitive performance, characterized by women not being able to learn as well as they had during premenopause. Improvement did rebound to premenopausal levels in postmenopausal women, suggesting that menopause transition-related cognitive difficulties may be time-limited. The initiation of MHT prior to the final menstrual period had a beneficial effect, whereas initiation after the final menstrual period had a detrimental effect on cognitive performance (42).

Dementia and Alzheimer's disease

The most common form of dementia is Alzheimer's disease (AD) which is 3 times more common in women than in men. Women with preexisting dementia or AD have been noted to have lower serum estradiol levels than women without dementia (43). In observational studies, less AD has been observed in postmenopausal women who use estrogen and the effect was greater with increasing duration of use (44-45). In some trials, women with mild to moderate AD who were given estrogen had improvement in their dementia (46-47) but this was not observed in all clinical trials (48-49).  Estrogen has been believed to help prevent AD by regulating synapse formation in the hippocampus and by inducing acetycholinesterase and choline acetyltransferase, both of which are important in memory (50). Estrogen may also improve cognitive function because of protection against neuronal toxicity caused by oxidation and increasing metabolism of serum amyloid P (51). However, in the WHI Trial, hormonal treatment with either (CCE+MPA) or (CCE) alone was found to double the risk of AD and mild cognitive impairment.  These findings cast doubt on a long- term role of estrogen in the prevention or treatment of AD. However, considerable controversy exists, as the sensitivity of the testing used in the WHI may not have been adequate to detect early disease, and it is well known that once a woman is affected by AD, estrogen is unlikely to provide any benefit (52).

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. A double-blind randomized trial of postmenopausal women with decreased libido who received 4 months of oral estrogen and methyltestosterone showed that this treatment significantly improved libido (53). Another study evaluated a group of women who had bilateral oophorectomies and who were subsequently treated with oral estrogen and either placebo or transdermal testosterone in varying doses. In the group treated with testosterone, sexual function improved (54). Initially, published studies had shown the efficacy and short-term safety of use of a transdermal testosterone patch for the treatment of hypoactive sexual desire disorder in menopausal women using concomitant estrogen (55). A follow-up double-blinded, randomized, placebo-controlled study known as APHRODITE (A Phase III Research Study of Female Sexual Dysfunction in Women on Testosterone Patch Intrinsa, for the treatment of hypoactive sexual desire disorder in 814 menopausal women who were not receiving estrogen or estrogen plus progestin. This was a 52 week trial where women were randomly assigned to receive either a patch delivering 150 or 300 "g of testosterone per day or placebo.  Evaluation at week 24 of use demonstrated that the women on the 300 "g testosterone patch noted a significantly greater increase in the 4-week frequency of satisfying sexual episodes in comparison to the placebo group, but this was not observed in the group receiving 150 "g per day. As compared with the placebo group, both doses of testosterone patches were associated with significant increases in desire. The rate of androgenic adverse events was noted to be higher in the group receiving 300 "g of testosterone per day than in the placebo group. Furthermore, breast cancer was diagnosed in 4 women who received testosterone (as compared with none who received placebo) (56). The excess cases of breast cancer in women treated with testosterone may be due to chance. However, the possibility of a causal relationship must be considered as several published studies have shown that higher levels of endogenous and administration of exogenous testosterone is associated with the risk of breast cancer (57-58). Clearly, long-term data from large clinical trials using testosterone are lacking and are needed.  At the present time the risk-benefit ratio of testosterone is too unclear to justify its prescription.

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 with a lifetime risk of breast cancer in 1:8 women (59).
Risk factors for breast cancer include the following:

• age
• age at the start of menstruation
• age at first live birth
• number of first-degree relatives (mother, sisters, daughters) with breast cancer
• number of previous breast biopsies (whether positive or negative)
• at least one breast biopsy with atypical hyperplasia
• presence of inherited gene mutations (BRCA1 or BRCA2 gene)

Other risk factors, such as age at menopause, dense breast tissue on a mammogram, use of birth control pills or MHT, a high-fat diet, drinking alcohol, low physical activity, obesity, or environmental exposures, are not included in risk estimates with the Breast Cancer Risk Assessment Tool for three reasons: evidence is not conclusive or current data cannot accurately determine how much these factors contribute to the calculation of risk for an individual woman, or adding these factors does not increase the accuracy of the tool appreciably.

Breast Cancer and MHT

Combined estrogen and progesterone treatment increases a woman's risk of developing breast cancer. The WHI trials demonstrated an increased risk of developing invasive breast cancer after 3 years of MHT use, with an unadjusted hazard ratio of 1.26 over 5.2 years of average follow-up (60). 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 10 or more years were at greatest risk followed by patients using MHT for 5 to 10 years. Women who took MHT for less than 5 years had only a slight increase in risk. No correlation between risk factors--a patient's age, ethnicity, the 5 year Gail model risk score, body mass index (BMI) or family history-- and the development of breast cancer was noted. In women who had undergone hysterectomy and were randomized to CEE alone, no increase in breast cancer risk was observed; a decreased risk, though not statistically significant, was observed in this group (61).
One of the ways in which MHT might increase breast cancer is by increasing breast density. It has been noted that estrogen with cyclic micronized progesterone resulted in 16.4% more women with increased breast density (62).  A subset of 307 women in The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was studied to examine the effect of MHT on mammograms. Of the group of women taking unopposed estrogen, 3.5% had an increase in breast density. Of the women taking both estrogen with progestin therapy, a 19.4-23.5% increase in breast density on mammography was noted, depending upon whether they took cyclic versus continuous MPA (63).  As such, it can be easily stated that mammographic density is a strong independent risk factor (6-fold) for the development of breast cancer.
Although some studies have suggested 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 (64), clinical trial data from the WHI do not support this conclusion. 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 (65). Taken together, these data suggested 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 (MPA + CEE) had a higher risk of invasive breast cancer. Tumors in the women taking combined MHT were comparable in histology and grade to the placebo group but were at a more advanced stage.

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 (66).
The Gail Model takes into account the following characteristics:

• age
• age at menarche
• age at first live birth
• number of first degree relatives with breast cancer
• number of previous breast biopsies
• number of breast biopsies that were hyperplastic

This model provides an individualized risk for developing breast cancer over the next 5 years and over a lifetime. Other prospective scoring systems have been developed, but as of this writing there is no other dominant system that has proven to be superior to the Gail Model. 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 a SERM (i.e.., tamoxifen or raloxifene) to protect against an excess risk of breast cancer. Moreover, women with a high risk of developing breast cancer should avoid MHT, despite the lack of definitive data on how much it may increase their risk of breast cancer (66).

Chemoprevention

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 estrogenic 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 May of 1999, the Study of Tamoxifen and Raloxifene (STAR) trial opened, having followed closely the National Surgical Adjuvant Breast and Bowel Project (NSABP)'s first breast cancer prevention clincial trial. This initial trial ran from April 1992 to 1998 and included 13,388 women who were at high risk for developing breast cancer. 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. Researchers found that of the women who were randomly assigned to Tamoxifen versus placebo, those who took Tamoxifen experienced a 49% decrease in the incidence of invasive breast cancer compared to those who received a placebo instead. In addition, there was a decrease in the risk of estrogen receptor positive breast cancer and nodal involvement in those with breast cancer. The study also demonstrated that women taking Tamoxifen had fewer diagnoses of non-invasive breast cancer, such as ductal carcinoma in situ (DCIS) (67).
The follow-up STAR trial investigated whether treatment with Tamoxifen and Raloxifene helped prevent breast cancer in women at high risk for disease. All participants received either tamoxifen or raloxifene and took the drug for 5 years. In 2006, the results of STAR show that both raloxifene and tamoxifen are equally effective in reducing breast cancer risk in post-menopausal women at increased risk of the disease. Women in the tamoxifen group and women in the raloxifene group had statistically equivalent numbers of invasive breast cancers (163 cases in 9,726 women in the Tamoxifen group versus 167 cases in 9,745 women in the raloxifene group). Tamoxifen is known to be able to reduce breast cancer risk by 49%, and this study shows that raloxifene can also reduce breast cancer risk by half as well. As such, these results led to the FDA's approval of raloxifene to help prevent invasive breast cancer in post-menopausal women at high risk of the disease (68).
Tamoxifen as a drug must be metabolized by the hepatic cytochrome P450 enzyme system, specifically cytochrome P450 2D6 (CYP2D6), to active metabolite endoxifen in order to have an affinity for the estrogen receptor. Consequently, therapy with drugs that inhibit CYP2D6 may reduce the clinical benefit of tamoxifen by interfering with its bioactivation, particularly when these drugs are used for an extended period.  A significant percentage of patients with breast cancer experience a depressive disorder and are prescribed an anti-depressant, most commonly one of the selective serotonin reuptake inhibitor (SSRI) category. This is particularly relevant in the context of tamoxifen therapy because SSRI anti-depressants inhibit CYP2D6 to varying degrees, specifically paroxetine is noted to be an irreversible inhibitor of CYP2D6. A population based cohort study was performed on 2430 women treated with tamoxifen and a single SSRI from 1993-2005. Of the group studied, 374 (15.4%) women died of breast cancer during follow-up. After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other anti-depressants. This is one of many articles clearly supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer (69).

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 measured beginning at age 35 years and every 5 years thereafter, the interval at which a periodic health examination has been advocated by the US Preventive Services Task Force (70).

Lower reproductive tract

The entire gynecologic tract contains estrogen receptors. As women become menopausal, the pelvic organs may be affected by the loss of estrogen resulting in vaginal atrophy, narrowing and shortening of the vagina and uterine prolapse, leading to high rates of dysparuenia. Furthermore, the urinary tract contains estrogen receptors in the urethra and bladder, and as the loss of estrogen becomes evident, patients may experience urinary incontinence (UI). While MHT is effective in reversing changes associated with vaginal atrophy (71-72). it does not seem to help with symptoms of UI. The WHI Clinical Trial found that women who received MHT and who were continent at baseline demonstrated an increase in the incidence of all types of UI at 1 year. The risk was highest for women in the CEE alone arm. Among women experiencing UI at baseline, the frequency of symptoms worsened in both arms and these women reported that UI limited their daily activities. This evidence clearly shows that the use of MHT increases the risk of UI among continent women and worsened the characteristics of UI among symptomatic women after 1 year of use.  Therefore MHT should not be prescribed as part of a regimen for UI alone (73). MHT is effective in the treatment of vaginal atrophy and dryness. For this purpose, systemic or vaginal estrogen can be used, though locally applied estrogen is recommended and can be administered in very low doses. These low doses 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 (74).

Adrenal gland

The adrenal gland is responsible for producing androstenedione, dehydroepiandrosterone sulfate (DHEA-S) and indirectly testosterone. After the menopausal years, androstenedione levels decrease by 62%, DHEA-S levels decline by 74% and testosterone, produced by the peripheral conversion of androstenedione, decreases by up to 25%. Levels of estrone, which is produced from the peripheral conversion of androstenedione, increase after menopause, whereas levels of estradiol, which is produced from the peripheral conversion of estrone, decline.  The menopause associated drop in estrogen is related to a significant decline in sex hormone binding globulin (SHBG), resulting in a higher free testosterone level. This may lead to mild increases in the amount of hair growth in postmenopausal women (75).

TREATMENT: Non-Hormonal

Vasomotor Symptoms

Selective Serotonin Reuptake Inhibitors (SSRIs)

When MHT is contraindicated,  (i.e., history of breast cancer), women with hot flashes may be treated with non-hormonal prescription drugs; one such class is the SSRIs (76). Once initiated, the relief of vasomotor symptoms usually occurs within a week, more rapidly than the relief of depressive symptoms, which usually takes 6 weeks or longer. The most common side effects of these drugs are nausea and sexual dysfunction but use of the lowest dose may minimize these effects.
Paroxetine and fluoxetine are SSRIs that have been used to treat hot flashes. Doses of either 12.5 or 25 mg/day of paroxetine 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 (77) . Furthermore, a randomized placebo controlled trial of 20 mg fluoxetine administration in 81 breast cancer survivors showed a reduction in hot flashes by 20% in women treated with fluoxetine for 4 weeks when compared to the placebo treated group (78). Though not as drastic of a reduction when compared to MHT, the SSRIs result in a modest improvement in symptoms.

Venlafaxine

Venlafaxine is a combined serotonin and norepinephrine reuptake inhibitor that has shown promise in reducing the severity of hot flashes in symptomatic women. A randomized trial was conducted in 229 women for 4 weeks where women received either varying doses of venlafaxine (37.5, 75 or 150 mg/day) versus placebo. There was a significant reduction in hot flashes in women receiving all doses of Venlafaxine in comparison to the placebo.  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 (79).

Gabapentin

Gapapentin is a newer therapeutic option for the treatment of hot flashes. A randomized, double-blind, placebo-controlled trial was conducted on 197 women aged 45-65 years, who were menopausal and having at least 14 hot flashes per week. These women were randomized to receive either gabapentin 900 mg daily or placebo for 4 weeks. Of women assigned to receive gabapentin, hot flash scores decreased by 51% as compared with a 26% reduction in the placebo group, from baseline to week 4. These women reported greater dizziness, unsteadiness and drowsiness at week 1 compared with those taking placebo; however, these symptoms improved by week 2 and returned to baseline levels by week 4 (80). A 2009 meta-analysis also confirmed similar results. Therefore, gabapentin seems to be an effective and well-tolerated treatment for hot flashes (81).

TREATMENT: MHT MHT has several beneficial effects. It relieves vasomotor symptoms and vaginal dryness caused by the loss of endogenous estrogen production. In addition, it acts like an anti-resorptive and is therefore osteoprotective and also has been shown to reduce the incidence of colon cancer by almost 40%. As mentioned earlier in this review, it is well established that 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 a uterus who were given estrogen alone in The Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial, 62% developed endometrial hyperplasia over 3 years. By identifying this pathology early, patients were medically treated with high doses of progestins so that no patients developed endometrial cancer (82). It is the standard of care to give women estrogen with a progestin when they have a uterus.
The decision to prescribe MHT must be based on each individual patient, taking into account the risk factors involved and creating a favorable benefit:risk ratio. To date, acceptable reasons to prescribe MHT include relief of severe vasomotor symptoms and to address vaginal atrophy. At present, there is no indication for using MHT for the prevention of cardiovascular disease, dementia/AD or osteoporosis or for the prevention of colon cancer, as the risks outweigh any potential benefits, although as mentioned earlier in this review, there are suggestions that MHT may show protective effects.
A key factor in the decision tree for the initiation of MHT is the individual risk of breast cancer, which is a real and serious concern. It is contraindicated to prescribe MHT to patients with a history of breast cancer and it is not recommended to give MHT to those with a high risk profile. The adverse events demonstrated in patients taking MHT included a 26% increase of invasive breast cancer, with the excess risk starting to be observed after 3 years of combined MHT use.
Recommendations for prescribing MHT should be based upon the randomized, clinical trial results of the WHI as highlighted throughout this review, as they currently constitute the best available medical evidence. Although the WHI studied the Prempro" formulation only, it is biologically plausible that other systemic formulations, including the transdermal patch, will carry similar risks and benefits and 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. Women that are currently on MHT and are asymptomatic, should be encouraged to discontinue MHT use. 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.

MHT regimens: continuous combined and cyclic regimens

There are many ways to prescribe MHT: oral tablets, patches, creams, sprays (Table 5). Considering the importance of including a progestin, there are several different modalities of administering the medications. This includes continuous combined and cyclical administrations. The continuous combined formulation administers both the estrogen and progestin hormones every day. The cyclical administration means that hormones are given in a cycle: 1) unopposed estrogen is given first 2) followed by estrogen combined with a progestin. This regimen can be a cycle 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 82.
In women just entering menopause, the cyclical administration of the estrogen and progestin is usually the simplest choice. These patients can easily make the transition from taking a low dose oral contraceptive pill in the menopausal transition (frequently prescribed to control the irregular vaginal bleeding during that time) to the cyclical form of MHT. At the onset of MHT, most women will experience 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. Although irregular vaginal bleeding is uncommon, any abnormal uterine bleeding should be investigated. Another advantage of the cyclical administration is that women will know when to expect bleeding.
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 on this regimen. 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.
Besides oral preparations, MHT can be administered in a variety of other ways. Estrogen can be delivered through a vaginal ring that delivers either 0.05 or 0.1 mg/day of estradiol acetate over a three month period. It may also be given transdermally as 17β-estradiol with norethinadrone acetate or levonorgestrel. Progesterone can be administered through a levonorgestrel-releasing IUD which can be left in place for 10 years. Finally, vaginal preparations of progesterone are also available. More recently, estrogen transdermal sprays and gels have come on to the market (Evamist ", Divigel, and Elestrin).  These preparations are relatively short acting and may be used 1-3 times per day.  All are FDA approved for the treatment of hot flashes.

Table 5. MHT FORMULATIONS
Trade Name	Estrogen	Progestin	Dose
Premarin	Conjugated Estrogen	-	0.3 to 1.25 mg PO daily
Cenestin	Synthetic Conjugated Estrogen	-	0.3 to 1.25 mg PO daily
Menest	Esterified Estrogen	-	0.3 to 1.25 mg PO daily
Estrace	17 β-estradiol	-	1-2 mg PO daily
Estinyl	Ethinyl estradiol	-	0.02 to 0.05 mg PO 1-3 x daily
Evamist	17 β-estradiol	-	1-3 sprays daily
Alora, Climara, Esclim, Menostar, Vivelle, Vivelle Dot, Estraderm	17 β-estradiol	-	1 patch weekly-twice weekly
Estrogel	17 β-estradiol	-	1.25 g daily transdermal gel (equivalent 0.75 mg estradiol)
Estrasorb	17 β-estradiol	-	2 foil pouches daily of transdermal topical emulsion
Activella	Estradiol 1 mg	Norethindrone Acetate 0.5mg	1 tab PO daily
FemHRT	Ethinyl Estradiol 5 mcg	Norethindrone Acetate 1 mg	1 tab PO daily
Ortho Prefest	17 β-estradiol 1 mg	Norgestimate 0.09 mg	First 3 tablets contain estrogen, next 3 contain both hormones; alternate pills every 3 days
Premphase	Conjugated Estrogen 0.625 mg	Medroxyprogesterone Acetate 5 mg	First 14 tablets contain estrogen only and remaining 14 tablets contain both hormones. 1 tab PO daily
Prempro	Conjugated Estrogen 0.625 mg	Medroxyprogesterone Acetate 2.5 or 5 mg	1 tab PO daily
Combipatch	17 β-estradiol	Norethindrone acetate	1 patch transdermal twice weekly
Climara-Pro	17 β-estradiol	Levonorgestrel	1 patch weekly
Estrace	17 β-estradiol vaginal cream		2-4 g daily x 1 week, then 1 g three times weekly
Premarin	17 β-estradiol vaginal cream		0.5 g daily for 21 days on, 7 days off or twice weekly
Vagifem	17 β-estradiol vaginal tablet		1 tablet per vagina daily x 2 weeks, then 2 times per week
Estring	Estradiol vaginal ring		1 ring inserted vaginally every 3 months

SUMMARY

In conclusion, this review has highlighted the major health concerns faced by the post-menopausal woman. Cardiovascular disease becomes more prevalent with the loss of estrogen and the decrease in HDL cholesterol levels that occurs concurrently with menopause. Osteoporosis is another serious potential problem that the aging woman faces and can be prevented by careful screening and early treatment. Cognitive decline and memory changes occur as aging ensues and AD becomes more prevalent, making it more difficult for aging women to maintain an independent lifestyle. Finally, breast cancer becomes more prevalent with advancing age. The increased risk of breast cancer needs to be considered when choosing a treatment plan for the post-menopausal woman.
There are a variety of treatments available to protect women from developing serious health problems. First and foremost, a healthy lifestyle is the best preventive medicine. MHT will control a patient's vasomotor symptoms, prevent bone loss, maintain a favorable lipoprotein profile and help prevent vaginal and urogenital atrophy. Other benefits of MHT include the reduction in the incidence of colon cancer. The SERM, raloxifene, also can be used to treat osteoporosis in menopausal women. The advantage of a SERM compared to MHT is its lack of endometrial stimulation and 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 with MHT.
The role of MHT has changed over the years as its risks were clarified through carefully designed randomized trials, most notably, the WHI trials. For a low-risk woman with moderate to severe vasomotor symptoms, the introduction of MHT is an option and patients will feel improvement in their symptoms. However, the clinician needs to evaluate each patient independently and take into account the individual risk profile including 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, non-hormonal alternatives are available and can also be used to treat symptoms.  Prudent clinical judgment and an individualized assessment of risks and benefits for patients using the currently available medical evidence remains the most appropriate approach.