LIPOPROTEIN CHANGES, CARDIOVASCULAR RISK, AND HT

The role of menopause in contributing to dyslipidemia has long been hypothesized. In women, total and low-density lipoprotein (LDL) cholesterol increase with age, and this increase is accelerated by menopause, whereas cardioprotective, high density lipoprotein (HDL) decreases. Moreover, the protective effect of HDL cholesterol appears to be diminished as women progress through menopause—possibly related to denser sub-particle size [27]. A rise in LDL has specifically been associated with the latter part of the menopausal transition and appears to be related to the loss of estrogen at this time of life [28]. In agreement with this finding is the relatively sharp upturn in CIMT observed in association with the late menopausal transition [29]. 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 [30].

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 HT, diet modification, and calcium and vitamin D supplements on CVD, 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 administered to women without a uterus, and a placebo arm involved both women with or without a uterus. The WHI findings suggest that administration of HT does not protect the heart. While the initial analysis showed that 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, 18-year cumulative follow-up showed no difference in CHD and CVD-related mortality [24]. Women who had higher baseline LDL cholesterol levels at the beginning of the study were at particularly high risk of CHD with HT use [31]. Although the expected changes in lipoproteins were observed with hormone therapy (decreased LDL and increased HDL), there was no associated reduction in CHD risk.

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 for ‘futility’. 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 [22].

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 coronary artery calcium (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 [32].

In conclusion, studies show that most women have minimal CAC and minimal increases in carotid IMT prior to menopause. The findings imply strongly 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 data, and secondary findings suggestive that early intervention with hormones may delay the onset of clinical heart disease, prescribing hormones for this purpose cannot be recommended based on the available data. These studies are unlikely to be the last word in this controversial field.

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, many procoagulation parameters improve, as evidenced by a decrease in fibrinogen and plasminogen levels; however, there is a higher risk for venous thromboembolism (VTE) due to increased liver metabolism of estrogen given orally [33].

HT in currently used doses is associated with an approximately 3-fold increase in VTE events. Transdermal estrogen preparations bypass liver metabolism and may be associated with the lowest VTE risk. Multiple observational studies have demonstrated fewer VTE and ischemic events with transdermal estrogen preparations compared to oral [34] [35-37]. SERM preparations also increase VTE risk. Tamoxifen increases VTE risk in a manner similar to oral estrogen, whereas raloxifene is associated with fewer VTE events than tamoxifen or estrogen [38, 39]. Bazedoxifene showed similar VTE risk compared to raloxifene in a randomized placebo-controlled trial [40]

OSTEOPOROSIS SCREENING

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 Absorptiometry (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 (WHO) 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

3.

osteoporosis as a T-score =< -2.5 SD

However, BMD via DEXA scan has a precision error of 2 to 6% depending on the site, which can amount to almost 1 t-score unit [44].

Bone density screening is useful, but does not provide all of the desired information about true fracture risk. Low bone density alone will not cause a fracture, unless it is so low that activities of daily living cause bones to break. Rather, women must have a combination of low bone density and a predisposition to falling that increases their risk. All major current guidelines state that BMD screening should begin at age 65 years for women of ‘average risk’ [45]. The rationale for waiting until age 65 to screen is that for most women, therapy will not need to be initiated before this time. Most guidelines also agree that BMD screening can and should be used selectively for women younger than 65 years if they are postmenopausal and have other risk factors for fracture (Table 1). Other considerations for BMD screening include estrogen deficient women of any age, vertebral anomalies and primary hyperparathyroidism.

In order to attempt to address the factors beyond bone density that can be used to predict fractures, the World Health Organization (WHO) 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 2. Clinicians can use the FRAX tool to make clinical decisions regarding BMD testing (http://www.shef.ac.uk/FRAX/index.aspx). FRAX can be used in women younger than 65 years to determine which women should have a BMD scan [46]. Those women with a FRAX 10-year risk of major osteoporotic fracture of 9.3% could justifiably be referred for DXA because that is the risk of fracture found in a 65-year-old Caucasian woman with no risk factors. It is important to note that FRAX does not provide data on fracture risk for women aged 40 or under.

While FRAX has been a highly utilized tool for clinicians, The American College of Physicians (ACP) recently suggested there is little evidence demonstrating effective treatment outcomes [47]. This limitation of the FRAX assessment was based on a randomized, controlled trial that showed that raloxifene significantly reduces clinical fractures in women ages 31-81 years but has similar efficacy regardless of a woman’s degree of fracture risk [48]. Ultimately when using screening tools, it is important for clinicians to take into account not only the age, but also presence of risk factors when deciding whom to screen for BMD testing.

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 they would if they remained sedentary [49]. The Institute of Medicine recommends women ingest 1200 mg of dietary calcium and 400 IU dietary vitamin D daily to help protect from menopausal bone loss [50]. Supplementation with calcium and vitamin D if dietary levels cannot be achieved has been recommended. However, concerns have been raised about calcium supplementation including increased risk of renal stones and cardiovascular events [51]. Data from several large clinical trials raise the possibility that a small but statistically significant risk for cardiovascular disease exists (Table 3). This risk does not seem to exist if a woman takes in calcium through dietary sources. It has been speculated that higher serum calcium levels are achieved with supplements but not when calcium is absorbed through consumption of calcium-rich foods, and that this transient; high circulating calcium can cause tissue calcification and dysfunction.

Such cardiovascular risk has not been demonstrated with vitamin D. Two recent controlled trials did not demonstrate increased cardiovascular events with use of high-dose vitamin D supplementation [61, 62]. However, guidelines do not currently support daily supplementation with calcium or vitamin D for primary prevention of fracture in postmenopausal women [45]. Practically speaking, patients should be encouraged to eat as many calcium and vitamin-D rich foods as they can through their diet. Those who have documented vitamin D deficiency should be given supplements.

TREATING OSTEOPOROSIS

Treatment for osteopenia and osteoporosis includes weight-bearing exercise, dietary modification, assuring adequate calcium and vitamin D intake, and the introduction of other medications. There are several different types of medications that can be used to treat low BMD: bisphosphonates, SERMs, calcitonin, hormones, and denosumab are all clinically-proven anti-resorptives (Table 4).

Although most fractures occur in women with bone density in the osteopenic range, it is

not recommended to treat osteopenia without additional features that carry a more worrisome prognosis for fracture [63]. The approved medications for both treatment and prevention of osteoporosis include bisphosphonates and the SERM, raloxifene. Bisphosphonates have been a mainstay of therapy for many years, and act by inhibiting bone resorption. Although they have a long track record of efficacy and safety, prolonged and high-dose usage has been associated with the rare side effects of osteonecrosis of the jaw and atypical femoral fracture [63]. Recent research indicates that bone density is maintained for several years after discontinuation of treatment, and ‘drug holidays’ may help reduce the risk of developing adynamic bone. Recent guidelines recommend treatment for 5 years and do not recommend additional BMD assessment during this time. Bisphosphonates should be avoided in women of child-bearing potential as they deposit in the bone, have a very long half-life, and accumulate in fetal bone if they are given to the mother.

Raloxifene acts like a pro-estrogen 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 mixed estrogen agonist 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 raloxifene treated patients [64]. Furthermore, a substantial decrease in the incidence of breast cancer was noted in raloxifene treated women, and the risk of having estrogen receptor positive invasive breast cancer was decreased when compared to placebo [65]. There was no difference between treatment groups with respect to the development of endometrial cancer.

For prevention of osteoporosis in postmenopausal or hypoestrogenic women, menopausal hormone therapy (when symptoms are present) or bazedoxifene/conjugated equine estrogens are appropriate agents [63]. A disadvantage of HT compared to bisphosphonates is the abrupt decrease in bone density that occurs when HT is stopped. Bazedoxifene is a SERM that has a similar profile to raloxifene, and thus, when combined with estrogen, appears to exert a neutral effect on the endometrium and can therefore be given without a concomitant progestin. This confers a significant advantage over HT for women with a uterus. This combination of SERM with estrogen, such as bazedoxifene with estrogen, is termed a tissue selective estrogen complex (TSEC). Bazedoxifene has a similar profile to raloxifene but has not yet been tested in a large clinical trial for outcomes related to breast cancer [66]. Thus far, clinical studies demonstrate no reports of breast concerns or benefits.

Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. This drug is approved for treatment, but not prevention, of osteoporosis. Denosumab can be given subcutaneously twice yearly to reduce the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis [67].

Parathyroid hormone (PTH) acts as an anabolic metabolite to stimulate bone production from osteoblasts, and is approved for treatment of osteoporosis. PTH decreases the incidence of new fractures and increases bone density. However, adverse side effects include hypercalcemia and gastrointestinal symptoms. Early rodent studies were concerning for possible bone tumor formation; however, post-marketing studies have not reported any cases. It remains that its approved use in humans is only for 24 months [68].

Calcitonin inhibits bone resorption, though not as effectively as other osteoporotic therapies. It is only available in intranasal or injectable forms as no effectiveness has been shown from oral formulations [69]. This is not generally considered first-line therapy but is a useful alternative when other medications are contraindicated.

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 in selected cases [67]. DEXA scans, although they are currently the best method for determining BMD, should not be repeated too frequently since errors in interpretation of trends can occur and lead to inappropriate therapy [70]. It is recommended that DEXA scans be repeated no more frequently than every 2 years.

MOOD

Significantly higher odds of depressive symptoms are reported by women who reach the late perimenopause. In the Study of Women’s Health Across the Nation (SWAN) [78], as well as 2 other longitudinal studies of the menopausal transition [79, 80], risk for depression was most pronounced in women who began the study with a low Center for Epidemiologic Studies Depression Scale score [78], indicating that the depressive symptoms were of new onset and appeared to be directly related to the menopausal transition. Follow-up studies using a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) confirmed that the late perimenopause is a vulnerable window for new-onset major depression [81]. The late perimenopause is also associated with a higher prevalence of sleep difficulty [82], which in turn is associated with depressive symptoms. Recent examination of anxiety symptoms in perimenopausal women indicate that, similar to depression, those with lower anxiety scores prior to the onset of the menopause transition are most vulnerable to a sudden escalation of anxiety and experience the greatest negative impact from their symptoms [83]. Not surprisingly, women with a lifetime history of anxiety and depressive symptoms during their menopausal transition report the lowest health related quality of life (HRQOL) [84], and poor sleep exacerbates these associations.

COGNITION

Women routinely complain of cognitive deficits around the time of menopause. Certain aspects of cognition appear to be related to a decline in estrogen, but many are simply related to the aging process itself. While some studies have demonstrated improved short term and verbal memory in postmenopausal women taking estrogen [85],others have not found such beneficial effects [86]. Greendale et. al. observed a sub-cohort of 2,362 SWAN participants longitudinally over 4 years to determine the effects of the menopausal transition and HT 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 rebounded to near-premenopausal levels once the transition was completed, suggesting that menopause transition-related cognitive difficulties may be time-limited. The initiation of HT prior to the final menstrual period had a beneficial effect, whereas initiation after the final menstrual period had a detrimental effect, on cognitive performance (68) [87]. More recently, the Cognitive Affective Study of the Kronos Early Estrogen Prevention Study (KEEPS-Cog) evaluated the impact of 4 years of HT on mood and cognition in early postmenopausal women. Various cognitive factors were not influenced by HT over 4 years, though a slightly positive effect on mood was observed in patients receiving oral conjugated equine estrogens. Mood and cognition did not differ between women receiving transdermal estrogen or placebo [88].

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 [89]. In observational studies, less AD has been observed in postmenopausal women who use estrogen and the effect was greater with increasing duration of use [90, 91]. In some trials, women with mild to moderate AD who were given estrogen had improvement in their dementia [92, 93], but this was not observed in all clinical trials [94, 95]. 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 [96]. Estrogen may also improve cognitive function because of protection against neuronal toxicity caused by oxidation and increasing metabolism of serum amyloid P [97]. However, these molecular findings do not appear to translate into clinical benefits, as the WHI’s Mental Status (WHIMS) Trial demonstrated that hormone treatment with either (CCE+MPA) or (CCE) alone doubled the risk of AD and mild cognitive impairment. These clinical trial findings do not support a long- term role of estrogen in the prevention or treatment of AD. However, considerable controversy remains, as the sensitivity of the testing used in the WHI may not have been adequate to detect early disease. As stated above, the KEEPS Trial did not note cognitive differences among women randomized to 2 types of estrogen plus progesterone or to placebo (86). This is noteworthy because KEEPS used a very detailed cognitive battery of tests.

LIBIDO

Loss of libido is a prevalent complaint in women of all ages and is present in approximately 9% of postmenopausal women [98]. Causes for a menopause-related decline in sexual interest may relate partly to a drop in both estrogen and testosterone with ovarian decline and aging, respectively. It is very important to consider the medication history and to screen for depression when clinically evaluating women with a complaint of diminished libido. In a survey of 35,381 women (the PRESIDE Study) [99], 10% reported decreased sexual desire; when women without concomitant depression or antidepressant medication were accounted for, the prevalence of desire disorder decreased to 6.3%.

Testosterone has long been considered as an agent that might promote libido in women. Several well-conducted, double-blind, randomized trials of testosterone in menopausal women with decreased libido have demonstrated small, but clinically and statistically improved symptoms [100]. Testosterone has been used as a transdermal formulation in most of these studies and demonstrates efficacy with or without concurrent use of estrogen, in women with and without their ovaries. The APHRODITE study examined transdermal testosterone in 814 menopausal women over 52 weeks. Women were randomly assigned to receive either a patch delivering 150 or 300µg of testosterone per day or placebo. Evaluation at week 24 demonstrated that the women on the 300µg testosterone patch noted a significantly greater increase in their 4-week frequency of satisfying sexual episodes in comparison to placebo, but this was not observed in the group receiving 150 µg per day. Both doses of testosterone patches were associated with significant increases in desire compared with placebo. Androgenic adverse events were greater in the group receiving 300 µg of testosterone per day. Breast cancer was diagnosed in 4 women who received testosterone (as compared with none who received placebo) [101]. 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 testosterone and administration of exogenous testosterone are associated with the risk of breast cancer [102, 103]. Clearly, long-term data from large clinical trials using testosterone are lacking and are needed [100]. Of note, a recent trial of a testosterone gel for female libido was discontinued because of lack of efficacy. There are no FDA-approved testosterone preparations available for women.

The only FDA approved medication for treatment of hyposexual desire disorder is flibanserin, marketed as Addyi. Flibanserin is a centrally-acting serotonin agonist/antagonist that increases female sexual desire and number of sexual acts [104]. These effects have been observed in the postmenopausal population, although it is not FDA-approved for this group of women. Adverse effects are generally mild and short-lived, except for a risk for hypotension and sedation if it is taken concurrently with alcohol, a problem that resulted in a black box warning and a need for prescribing clinicians to complete a risk evaluation and management strategy (REMS) certification before prescribing the drug [105]. Its effect size appears similar to that of testosterone (small, but statistically and probably clinically significant) [104].

BREAST CANCER AND HT

Combined estrogen and progesterone treatment increase a woman's risk of developing breast cancer. The WHI trials demonstrated a detectably increased risk of developing invasive breast cancer after 3 years of combined HT use, with an unadjusted hazard ratio of 1.26 over 5.2 years of average follow-up [107]. Technically, the 95% confidence interval included 1.00, thus, the data could be considered ‘not significant’; however, 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 HT use. Patients taking hormones for 10 or more years were at greatest risk followed by patients using HT for 5 to 10 years. Women who took HT for less than 5 years had only a slight increase in risk. No correlation was noted between other 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. In women who had undergone hysterectomy and were randomized to CEE alone, no increase in breast cancer risk was observed; in fact, a decreased risk was observed in this group after 18-year follow-up [24, 108].

One of the ways in which HT 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 [109]. A subset of 307 women in The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was studied to examine the effect of HT 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. Increased mammographic breast density is a strong independent risk factor (6-fold) for the development of breast cancer [110].

Case series and case-controls studies have suggested that patients taking HT who are diagnosed with breast cancer have a better prognosis than women not taking hormones, even when matched for stage of disease [111]. It has also been suggested that women who develop breast cancer while taking HT have their cancers detected at a more favorable stage and have less malignant disease [112]. These notions were disproven by the WHI Clinical Trial. Women randomized to combined HT with (MPA + CEE) had a higher risk of invasive breast cancer and mortality from 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 [107].

In contrast to combined E+P HT, E alone HT given to women without a uterus in the WHI, led to a decrease in breast cancer risk, which persisted after discontinuation of treatment and became statistically significant in the post-trial follow up study. After a median follow-up of 11.8 years, E alone treated women still had a lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62—0·95; p=0·02 [113].

SCREENING FOR BREAST CANCER

The lifetime risk of developing breast cancer is 12%. Various organizations recommend breast cancer screening for average-risk women (Table 5). These guidelines all suggest an individualized approach with patients that includes consideration of a patient’s risk factors, as well as shared decision making based on a discussion of risks and benefits of screening. For average-risk women, mammography is the recommended screening modality.

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 [117].

The Gail Model takes into account the following characteristics:

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

6.

Number of breast biopsies that were hyperplastic

7.

Race/ethnicity

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 to reduce her risk of breast cancer. Note that the Gail model does not factor into account breast density or HT use. It also does not account for mutations, such as BRCA1 or 2, which have a profound effect on a woman’s risk of contracting breast cancer. Other risk factors not included are history of chest radiation prior to age 30 and extreme breast density.

CHEMOPREVENTION

In women who are considered high risk for breast cancer, chemoprevention therapies are approved to reduce breast cancer incidence. These therapies include SERMs (Tamoxifen and Raloxifene) as well as aromatase inhibitors (Exemastane and Anastrazole) [118].

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. Raloxifene is also a SERM, but has the advantage of acting as an anti-estrogen at the level of the uterus. Tamoxifen was found to be effective in breast cancer prevention in a trial that included 13,388 women who were at high risk for developing 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. Women who were randomly assigned to tamoxifen experienced a 49% decrease in the incidence of invasive breast cancer compared to those who received a placebo. In addition, there was a decrease in the risk of estrogen receptor positive breast cancer and nodal involvement in those with breast cancer. Women randomized to tamoxifen also had fewer diagnoses of non-invasive breast cancer, such as ductal carcinoma in situ (DCIS) [119].

The STAR trial investigated the ability of tamoxifen compared to raloxifene in preventing 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 showed that both raloxifene and tamoxifen were 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 showed that raloxifene can also reduce breast cancer risk by half as well. As a result of this study, the FDA approved raloxifene as a second agent to help prevent invasive breast cancer in high-risk, post-menopausal women [120]. On an update of STAR trial, the risk ratio (RR; raloxifene: tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05–1.47) and for noninvasive disease, 1.22 (95% CI, 0.95–1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene: tamoxifen) were 0.55 (95% CI, 0.36–0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60–0.93) for thromboembolic events. There were no significant mortality differences [121].

To become active, tamoxifen must be metabolized by the hepatic cytochrome P450 enzyme system, specifically cytochrome P450 2D6 (CYP2D6), to its active metabolite, endoxifen. 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 in the selective serotonin reuptake inhibitor (SSRI) category. This is clinically relevant in the context of tamoxifen therapy, because SSRIs inhibit CYP2D6 to varying degrees. Paroxetine is an irreversible inhibitor of CYP2D6, and therefore has the greatest potential to disrupt the biological activity of tamoxifen. 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). No such risk was seen with other anti-depressants [122].

The effectiveness of aromatase inhibitors for reduction of breast cancer incidence has also been demonstrated. The MAP3 trial investigated the incidence of invasive breast cancer with exemestane versus placebo in 5,560 high-risk postmenopausal women for up to 5 years [123]. Exemestane significantly reduced invasive breast cancer by 65% compared to placebo (95% CI, 0.18-0.70). There were no cardiovascular or thromboembolic side effects. However, follow-up study demonstrated worsened BMD after 2 years in the treatment group regardless of calcium and vitamin D supplementation [124]. Thus, for women receiving this therapy, close BMD screening is important. Anastrazole for prevention of breast cancer in high-risk postmenopausal women was studied in the IBIS-II trial [125]. One thousand nine hundred twenty women were randomized to anastrazole vs placebo for 5 years. A 53% reduction in invasive cancer was seen in the anastrazole group (95% CI, 0.32-0.68). Women who were concurrently treated with a bisphosphonate did not have significant bone loss, but the anastrazole-only group demonstrated worsened BMD after 3 years [126].

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

When HT 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 [140, 141]. 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.

Though not as drastic of a reduction when compared to HT, the SSRIs result in a modest improvement in symptoms. A long-acting mesylate salt of paroxetine, 7.5mg, has been FDA-approved to treat hot flashes [142]. Non-approved SSRIs that have been tested and have clinical efficacy include paroxetine (non-mesylate), escitalopram, citalopram, fluoxetine and sertraline [141].

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)

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 with breast cancer 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 placebo. Common side effects included nausea or vomiting, which are usually limited to the first 1 to 2 weeks of treatment. Other side effects include lethargy, dizziness, constipation and sexual dysfunction [143].

GABAPENTIN

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 [144]. A 2009 meta-analysis confirmed consistency across several clinical studies [145]. The dose range of gabapentin is broad, and although many clinical trials use doses of 900 mg, less may work well for individual patients. The chief limiting side effects of gabapentin are drowsiness, dizziness (which can present a hazard for falls), and weight gain.

NEUROKININ B RECEPTOR (NK3R) INHIBITORS

Neurokinin B acting on its receptor, NK3R, at the level of the hypothalamus induces vasomotor symptoms typical of menopause. It is hypothesized that variable expression of NK3-R and interaction with its ligand is responsible for the differences in reported hot flashes experienced by menopausal women. The TACR3 gene codes for NK3-R. Genome-wide association studies performed on 17,695 women from the WHI trial and observational studies demonstrated significant genetic variation in TACR3 in women who reported vasomotor symptoms [146]. An oral NK3R antagonist completed phase II clinical trials and demonstrated a 45% decrease in the number of hot flashes per week as compared with placebo [147]. This drug is not associated with the side-effects of estrogen therapy, and further study will determine its efficacy and safety for use.

NON-PHARMACOLOGIC

Non-pharmacologic options for treatment of menopausal symptoms have yet to show proven benefit in large clinical trials. There are mixed results from trials evaluating the benefits of acupuncture for treatment of menopausal symptoms including vasomotor symptoms, insomnia and mood. As acupuncture is a generally low-risk therapy, it is at the discretion of the patient to pursue this treatment modality, but effectiveness in large trials is lacking. Phytoestrogens, which are estrogen-like compounds found in products such as soy, have no proven benefit in treatment of menopausal symptoms. Chinese herbal remedies likewise have not been shown to significantly alleviate symptoms, with or without acupuncture. The MsFLASH trial is a randomized controlled trial that showed reduction of insomnia in peri- and post-menopausal women with hot flashes who were treated with cognitive behavioral therapy for insomnia (CBT-I) compared to menopause education control [148]. Women who practiced CBT-I had significant reduction of insomnia after the 8-week intervention, and these results persisted at 24-week follow-up despite having no effect on daily hot flash frequency. Practical daily lifestyle habits including exercise, dressing in layers, consuming cold drinks, avoiding caffeine and alcohol may help alleviate symptoms.

HT REGIMENS: CONTINUOUS COMBINED AND CYCLIC REGIMENS

There are many ways to prescribe HT: oral tablets, patches, creams, sprays (Table 6). Considering the importance of including a progestin, there are several different modalities of administering these medications as well. This includes continuous combined and cyclical administrations. The continuous combined formulation administers both the estrogen and progestin hormones every day. Cyclical administration means that hormones are given in a cycle: 1) unopposed estrogen is given continuously 2) progestin is added. 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 [151].

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 HT. At the onset of HT, 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 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, HT 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 norethindrone acetate or levonorgestrel. Progesterone can be administered through a levonorgestrel-releasing IUD which can be left in place for up to10 years. Finally, vaginal preparations of progesterone are also available. More recently, transdermal estradiol sprays and gels have been FDA approved (Evamist ®, Divigel, and Elestrin). These preparations are relatively short acting and sometimes need to be used more than once a day. All are FDA approved for the treatment of hot flashes.

TSECs—TISSUE SPECIFIC ESTROGEN COMPLEXES

The combination of bazedoxifene/conjugated equine estrogens represents yet another novel approach to hormone therapy. The combination of bazedoxifene, a SERM, with estrogen allows the clinician to apply estrogen where it is most beneficial—reducing or eliminating hot flashes, while the SERM bazedoxifene exerts anti-estrogenic effects at the target tissues where estrogen action is unwelcome—the endometrium and the breast [66]. Thus, the combination of bazedoxifene and conjugated equine estrogens is effective as an antiresorptive agent in bone and does not cause endometrial stimulation. With the bazedoxifene/conjugated equine estrogen combination, the clinician can avoid having to give progestin and avoid irregular or breakthrough bleeding.