Menopause

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Chapter 188 Menopause

image Introduction

Menopause denotes the cessation of menstruation in a woman, which usually occurs when she reaches the age of 51 years. Twelve months without a spontaneous period is the commonly accepted rule for diagnosing menopause. The time prior to menopause is referred to as perimenopausal, whereas the time after menopause is referred to as postmenopausal. During the perimenopausal period, women ovulate irregularly, infrequently, or not at all; therefore, they begin to experience changes in the menstrual cycle with or without other symptoms.

With the prolongation of life expectancy, the menopausal and postmenopausal periods are becoming more significant in a woman’s life. In fact, today’s average woman can expect to live at least one third of her life in the postmenopausal stage.

By the year 2015, nearly 50% of the women in the United States will be menopausal. Between 1990 and 2020, the menopausal population in the country will double. This dramatic rise in the number of menopausal women is changing the way health care providers work with women and changing medicine itself. At no other time in history have so many individuals been dealing with the same set of health issues. Now more than ever, clinicians have options for the management of menopause.

Current conventional medical treatment of menopause primarily involves short-term (1 to 4 years) hormonal therapy (HT) for the primary indication of moderate to severe vasomotor symptoms, using estrogen with or without a progestogen. The obvious question is “Is hormone replacement therapy necessary?” The goal of this chapter is to answer this question and offer an approach to perimenopause and menopause that provides many different options.

image General Considerations

The goals of an integrative medicine approach to menopause are to provide relief from common menopausal symptoms and to prevent and/or treat osteoporosis, cardiovascular disease, and other diseases of aging while minimizing the risks of breast cancer, coronary heart disease (CHD), venous thromboembolism, strokes, and gallbladder disease. The evaluation process reveals a woman’s perimenopausal/menopausal symptoms, other acute and chronic health problems, health habits, mental/emotional stressors, and risks for future diseases.

One of the most complicated and difficult health care decisions that menopausal women face today is whether to use HT. Women look to their health care providers for definitive answers to these questions. Practitioners are faced with an even greater challenge: evaluating the benefits and risks of conventional hormone therapy (cHT) and natural hormone therapy (nHT) for an individual patient.

In the year 2000, some 46 million prescriptions for conjugated estrogen (Premarin) were written in the United States. An additional 22.3 million prescriptions were written for the same preparation with medroxyprogesterone (PremPro). Almost one in three women given a prescription for cHT never has it filled. Of those who do start cHT, the majority discontinue its use shortly after starting therapy. Reasons given for discontinuing the drug include uterine bleeding; side effects including mood changes, breast tenderness, bloating, and weight gain; a fear of breast cancer; and not understanding or believing in the need for its long-term use. Lack of compliance can also be attributed to inadequate education of many health care practitioners regarding the needs of menopausal women, both gynecologic and nongynecologic. Many practitioners also have a limited understanding of the many therapeutic options for menopausal symptoms and of the more global issues of menopause. In addition, holistic menopause practitioners who use both cHT and nHT hold that compliance improves with the use of nHT and that many side effects disappear or improve when patients switch from cHT to nHT.

Sadly, many menopausal women have a limited understanding of the long-term health risks associated with this change in hormone status, and very few women believe that they are well informed about the benefits and risks of cHT or nHT. Each woman wants to know whether HT is right for her—how she may benefit, how long she will have to take the drug to receive those benefits, and what the short-term side effects as well as the potential long-term negative effects are.

Scientific evidence regarding the use of postmenopausal HT comes in many shapes: observational studies, large-scale randomized trials, small clinical trials, biological plausibility, in vitro studies, and animal studies. Other factors involved in the hormone conundrum are theoretical questions, areas of scientific uncertainty, popular consumer opinions and fears, and history. Definitive evidence for the benefits and risks of HT has been clarified by the two Heart and Estrogen/Progestin Replacement Studies (HERS I and HERS II) and the Women’s Health Initiative (WHI). Another large-scale trial conducted in 14 countries, the Women’s International Study of Long Duration Oestrogen after Menopause (WISDOM), was discontinued in November 2004 for scientific and practical reasons. Because WISDOM was to be completed after the publication of WHI results, “there were no safety concerns for the 5700 women enrolled in the study. However, the trial was not expected to provide substantial evidence that would have an impact on clinical practice decisions in the next 10 years.”1

The North American Menopause Society has a very comprehensive position statement, last updated in 2010.2 In summary, this document says that although there are many benefits (with regard to vasomotor symptoms, urogenital atrophy, urinary health, osteoporosis, and reduction in the onset of type 2 diabetes mellitus), there are also slight statistical risks (of breast cancer, stroke, venous thromboembolism, and ovarian cancer). A still unfolding picture focuses on cardiovascular disease, cognitive decline, and dementia.

The bottom line is that women and their health care practitioners are faced with trying to make the best decisions possible on the basis of what we do know, what we do not know, and what we are still uncertain about.

Benefits

Symptoms

The decline of endogenous estrogen leads to multiple tissue and organ changes and problems. In addition to the reproductive and urinary tracts, estrogen-sensitive tissues are skin, bone, vascular lining, teeth and gums, eyes, the brain, and the central nervous system.

Some 50% to 80% of women in the United States report menopause-related hot flashes, night sweats, vaginal dryness, insomnia, mood swings, and depression. During the first 5 to 10 years of menopause, vulvovaginal symptoms begin to appear. Later, as the other mucous membranes of the urogenital tract become affected, rates of incontinence and infection rise.

There is strong evidence and data from randomized clinical trials that estrogen therapy is very effective in controlling vasomotor and genitourinary symptoms. Vaginal estrogen is as efficacious as oral or transdermal estrogen for genitourinary symptoms and may be an advantageous method because of the local delivery and effect.

Sex steroids also affect sleep, libido, cognitive function, motor coordination, and pain sensitivity. Data are mixed regarding the role of menopause in depression and mood swings; however, depression and mood disorders appear to be more common or at least exacerbated in perimenopause or early menopause compared with the reproductive period, and HT benefits many women.

The North American Menopause Society and its advisory panel published a post-WHI report and recommendations on postmenopausal HT. One of its basic recommendations is that the treatment of menopausal symptoms (especially vasomotor and urogenital) remains the primary indication for HT or estrogen replacement therapy (ERT).

Osteoporosis

Estrogen is known to inhibit the age-related bone loss that occurs in most menopausal women. Observational studies have indicated that the use of estrogen reduces the risk of vertebral fracture by approximately 50% and the risk of hip fracture by 25% to 30%.3 Estrogen has been considered the therapeutic agent of choice for both the prevention and treatment of postmenopausal osteoporosis in women for many years—until the WHI results. It has been the most studied agent for prevention and has been shown to decrease bone resorption, prevent osteoporosis, and reduce fractures. Nevertheless, the U.S. Food and Drug Administration (FDA) has removed estrogen from the list of agents approved as effective in treating women who already have osteoporosis. This decision has nothing to do with any new discovery of a decrease in effectiveness for this indication; rather, it arose as an issue of fairness in new standards that have been applied to approving other drugs for osteoporosis treatment, such as the bisphosphonates (risedronate and alendronate). These agents have involved prospective fracture reduction studies on women with low bone mass and/or fracture. The data on estrogen treatment for existing osteoporosis are largely observational and retrospective in nature. These studies do demonstrate the efficacy of estrogen in treating patients with osteoporosis, but randomized clinical trials will be required before the FDA reinstates its indication.4

That being said, the WHI was a large clinical trial in which 16,608 postmenopausal women 50 to 79 years of age were studied at 40 U.S. clinical centers.5 The regimen used, was continuous combined estrogen-progestogen therapy (CCEPT) (e.g., PremPro). Women in the CCEPT group experienced lower rates of hip fracture (10 per 10,000 person-years vs 15 per 10,000 person-years in the placebo group, a 34% lower relative risk) and vertebral fracture (9 events per 10,000 women annually vs 15 events per 10,000 women annually for placebo, also a 34% lower relative risk). Statistically significant fracture reductions were also seen in other osteoporotic fractures (23%) and total fractures (24%).

The different estrogen agents approved for the prevention of osteoporosis and their antiresorptive effects are as follows:

It is important to keep in mind that some women derive benefits from these doses, some will need higher doses, and others will have adequate bone protection with lower doses. Dual-energy x-ray absorptiometry (DEXA) scans provide the most reliable objective information on the status of bone mineral density.

Colorectal Cancer

Accumulated observational studies now suggest that the use of ERT reduces the risk for colorectal cancer as well as the risk of dying from colon cancer.6 Although not all study findings are consistent, some studies have shown that the risk of developing fatal colon cancer was reduced by 33%7; others show as little as an 8% reduction in risk.8

Risks

Endometrial Cancer

Unopposed estrogen administration is associated with an increase in the risk of endometrial cancer by a factor of 8 to 10. This results in an excess of 46 cases per 10,000 women for women who use unopposed estrogen for at least 10 years.9 The risk decreases after discontinuation of the ERT, but it is still elevated after more than 10 years. Adding a proved dose and delivery method of a progestogen (progestins or progesterone), which opposes the effects of estrogen on the endometrium, reduces the risk to a minimum and is essential to preventing endometrial hyperplasia and endometrial cancer.

A boon to the use of natural hormones, particularly oral micronized progesterone (OMP), came in the form of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial and its study of the effects of HT on endometrial histology in postmenopausal women.10 This trial confirmed that daily CEE, 0.625 mg, enhanced the development of endometrial hyperplasia, and that combining CEE with cyclic or continuous medroxyprogesterone acetate (MPA) protected the endometrium from hyperplastic changes. What was new was that the trial also concluded that cyclic OMP (200 mg daily for 12 days per month) also protected the endometrium from the hyperplastic changes associated with estrogen-only therapy. Thus, the PEPI was the first clinical trial proving that OMP was as appropriate as MPA for use in the protection of the endometrium. Compounded OMP was already available, but the product Prometrium came on to the market as a result of that study.

Venous Thromboembolism

Venous thromboembolism (VTE) is an almost expected complication of the postmenopausal use of exogenous hormones. Observational studies have demonstrated that in postmenopausal women who use ERT, the risk of VTE is increased by a factor of 2 to 3.5. These observations are consistent with the data found in HERS I (discussed later). The investigators reported that the risk of thromboembolic events was increased by a factor of 2.7 in the women receiving the estrogen-progestin therapy.7 HERS II showed that the relative risk (RR) of VTE increased 108% (RR 2.08) and the absolute risk was 0.59% in the HT group compared with 0.29% in the placebo group (59 events vs. 28 events annually per 10,000 women, respectively).11

The WHI reported similar results. The relative risk was 2.11 in the HT group, a 111% increased risk. The absolute risk was 34 events in the HT group compared with 16 events in the placebo group per 10,000 women.7 Owing to the uncommon presence of idiopathic venous thromboembolism in women above 50 years of age, the absolute risk associated with postmenopausal HT is pretty small. For women who are already at risk for thromboembolism or who are older, the absolute risks of HT will be higher.

Coronary Heart Disease

For the past 30 years, practitioners have been advising menopausal women that HT reduces the risk of CHD. More than 40 observational studies in these past three decades have suggested that this risk is 35% to 50% lower among women who take estrogen than in women who do not.12,13 These observational data have been reinforced by additional research demonstrating some of the impact of estrogen on individual factors known to be associated with CHD, thereby also establishing a biologically plausible mechanism for the association of HT and reduced CHD. Randomized trials have shown that estrogen therapy reduces plasma levels of low-density-lipoprotein cholesterol (LDL-C) by 10% to 14% and raises plasma levels of high-density-lipoprotein cholesterol (HDL-C) by 7% to 8%.7,14 Estrogen has also been shown to reduce Lp(a) lipoprotein, inhibit oxidation of LDL-C, improve the endothelial vascular function, reduce fibrinogen, and reduce thickening in the arterial walls.

However, estrogen may have detrimental effects on cardiovascular risk markers, as by raising triglyceride levels, increasing clotting, and raising levels of C-reactive protein. These detrimental effects of estrogen may override the beneficial effects of estrogen on cardiovascular function and may explain the surprising results of randomized, placebo-controlled trials indicating that HT did not reduce the overall rate of CHD. In HERS II and the WHI, it actually increased the rate of CHD. These new data from randomized trials, compared with the 30 years of observational data and the biologically plausible mechanisms, have rendered recommendations to postmenopausal women about HT more complex and challenging. Both patients and practitioners have questions with no clear-cut answers, and concerns about the benefits and risks of HT are more difficult to sort out.

Heart disease is the leading cause of morbidity and mortality in women, and an understanding of the current state of the evidence and the potential for the cardioprotective effects of HT, as well as the cardiovascular negative effects of HT, is of vital importance to women’s health. In this discussion, however, one must not forget the potential cardioprotective effects of nutrition, exercise, stress management, and select nutrients such as niacin, magnesium, and fish oils.

The basic problem with HT and CHD is that the later randomized trials of estrogen among women with preexisting CHD have not confirmed the 40 observational studies of the last 30 years. The first large-scale randomized double-blind placebo-controlled trial of HT (a combination of CEEs [Premarin] and CEEs with medroxyprogesterone acetate [Provera]) for the secondary prevention of CHD was the Heart and Estrogen/Progestin Replacement Study (HERS I).7 In a total of 2763 women with established CHD studied at 20 clinical centers throughout the United States, the death rates from coronary causes and nonfatal myocardial infarctions in the hormone group and the placebo group were similar. Perhaps more worrisome was the 50% increase in the risk of CHD events (thromboembolism) during the first year in the women receiving HT. The HERS I data prompted a barrage of questions, as follows:

A brief attempt at some answers was made after HERS I: The early risk for increased CHD events in the hormone-treated group has been a pattern seen in subsequent studies—the Puget Sound Group Health Cooperative of Seattle,15 the Nurses’ Health Study,16 and the early data from WHI.17 An early risk for blood clots in the legs and lungs, heart attack, and stroke appears to be a real phenomenon in postmenopausal women who begin HT. Two hypotheses to explain this finding are that estrogen has a prothrombotic effect and a proinflammatory effect on the vascular endothelium.

There indeed may be some subgroup of women with a predisposition for the prothrombotic and/or proinflammatory effects of estrogen—for example, women with hyperinsulinemia, hypertension, elevated homocysteine levels, increased C-reactive protein and Lp(a) lipoprotein levels, obesity, and/or elevated LDL-C. Interestingly, in the HERS I trial, differences were observed between hormone-treated women who also took lipid-lowering therapy (statins) and hormone-treated women who did not. The rate of CHD events after 1 year was much lower in the HT-plus-statin group than in those who did not use statins. The same was true for risk of venous thromboembolic events.

Another controlled trial attempted to address the question of whether estrogen inhibits atherosclerosis. In the placebo-controlled Estrogen Replacement and Atherosclerosis (ERA) trial, neither estrogen alone nor estrogen plus the progestin18 affected the progression of coronary atherosclerosis. Plasma levels of LDL-C were reduced by 9.4% in the unopposed estrogen group and by 16.5% in the estrogen-plus-MPA group. Both groups had significant increases in HDL-C (18.8% and 14.2%, respectively) compared with the placebo group. The two estrogen groups had rises in triglyceride levels (6.1% and 10.1%, respectively), but these changes were not significantly different from the levels in the placebo group. The ERA trial provided the first anatomic endpoint (angiographically determined effects on coronary arteries) in women who had known CAD. The ERA trial supported the overall null effect found by the HERS I trial and also showed that the MPA did not cancel out the beneficial effects of estrogen, as was suspected in the HERS I trial. These data and other study results indicate that HT does not have a significant impact on the progression of atherosclerosis in women with established heart disease.

Preliminary data from the Papworth Hormone-Replacement Therapy Atherosclerosis Study (PHASE), a small clinical trial in 225 postmenopausal women with angiographically proved CAD, showed no cardiovascular benefits of HT and also possibly a slight increase in the rates of cardiovascular events during the first 2 years of HT.19 This trial evaluated transdermal natural estradiol alone or with norethindrone, a different progestin.

An interim analysis of the WHI data also suggested that there had been a slight increase in the number of heart attacks, strokes, and thromboembolic events during the first 1 or 2 years in postmenopausal women undergoing HT.20

One clinical trial looked at estrogen use in postmenopausal women without clinical coronary disease. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was designed to determine whether unopposed natural estradiol reduces the progression of subclinical atherosclerosis.21 Postmenopausal women with high cholesterol levels but no preexisting cardiovascular disease, diabetes, or smoking history received either oral micronized natural estradiol or placebo and also lipid-lowering medication if serum LDL-C exceeded 160 mg/dL. The women were monitored for 2 years. The investigators evaluated the rate of change in carotid artery intimal-medial thickness. Women in the placebo group had an expected progression in the thickening of the carotid arteries over the 2 years. The women taking estradiol had a small amount of regression of the thickness of the carotid arteries. In women not receiving lipid-lowering therapy, the placebo group had a greater progression and the estradiol group had no progression of intimal-medial thickness—a dramatic difference. Curiously, in the women who received lipid-lowering drugs, there was no difference in the rate of progression between the women receiving estrogen and those receiving placebo.

On the basis of data from these randomized clinical trials conducted before HERS II and WHI, HT did not appear to reduce the risk of cardiovascular events in postmenopausal women who already had CHD. Then along came the world-shifting news in July 2002, when the results of HERS II and the WHI were published less than a week apart.

HERS II investigated the effects of 0.625 mg of CEE plus 2.5 mg of MPA on the prevention of CHD in older U.S. women (average age 71 years) with preexisting CHD.11 This study, a continuation of HERS I, was intended to determine whether a trend toward prevention of heart disease would appear if the study were continued longer. Once again, though, the results were not positive for women with heart disease. In HERS II there were no significant decreases in rates of primary CHD events (or strokes or clots) among women assigned to the HT treatment group who had already had CHD before starting the HT regimen (RR, 1% decreased risk and absolute risk of 3.66% for HT vs. 3.68% for placebo). The investigators concluded that “postmenopausal hormone replacement therapy should not be used to reduce the risk of CHD events in women who already have CHD.”11

A few days later, results of the landmark WHI study were published.5 The WHI investigated the effect of the most common HT regimen in the United States (0.625 mg Premarin plus 2.5 mg Provera, or PremPro) on the incidence of heart disease, breast and colorectal cancers, and fractures in postmenopausal women. The cardiovascular research was intended to investigate the effect of this HT regimen on the prevention of CHD in healthy postmenopausal U.S. women (aged 50 to 79 years) who do not have CHD. After a mean of 5.2 years of follow-up, the trial was stopped earlier than planned for the women using combined HT (mostly owing to harm from breast cancer incidence). In the WHI, there was a significantly higher risk of CHD annually per 10,000 women: a 29% increase in the relative risk and 37 more events in the HT group compared with 30 events in the placebo group. These findings, showing that estrogen plus progestin does not confer benefit in preventing CHD among women with a uterus, concurs with the HERS findings among women with clinical CHD as well as those of the ERA trial and others. The WHI results extend the findings of the earlier trials to include a wider range of women.

Stroke

In the WHI, there was no excess risk of stroke in the estrogen-plus-progestin group in the first year, but such a risk did appear in the second year, and it persisted.22 The mechanism does not seem to be related to an increase in blood pressure. The WHI findings were consistent but more dramatic than those of the HERS, which reported a nonsignificant 23% increase in the treatment group.11 WHI results were also more extreme than those of the Women’s Estrogen for Stroke Trial (WEST) of estradiol (without progestin) in women with a history of a prior stroke. Overall, the WEST trial found no effect of estrogen on recurrent strokes but some rise in rates in the first 6 months.23 Some might criticize the WHI statistics because they include older women. However, there was no indication that excess strokes were more likely to occur in older women, in women with prior stroke, through differences in race/ethnicity, or in women with high blood pressure. It is apparent that estrogen plus a progestin increases the risk of stroke in women who have been judged to be healthy. The estrogen-only arm of the WHI showed a slight increase in stroke for women in the youngest age group at study entry.24 The ERT arm was quite different from the HT arm.

One of the most recent studies on estrogen leads us to the most provocative question: Do different kinds of estrogens have different effects? In this study, the risk of VTE was compared among those who used esterified estrogen, conjugated equine estrogen, and no estrogen at all.25 The findings concluded that CEE but not esterified estrogen was associated with venous thrombotic risk.

Areas of Uncertainty

Breast Cancer

Fears about breast cancer and higher risk of breast cancer from HT dominate many women’s decision-making process about menopause management. Clinicians must be educated about this topic and must be prepared to summarize the results of relevant research in order to counsel each woman about the benefits and risks in her particular situation.

It is true that there are unanswered questions about the long-term safety of HT, especially regarding the risk of breast cancer. What is often forgotten is that the clinical trials data on ERT span the last 100 years. No other pharmacologic agent has been as thoroughly studied as estrogen. A half-century of research preceded the early 1940s, when HT became commercially available. Even though patient fears are high and alternative practitioners are particularly suspicious and skeptical about its safety, no data clearly and consistently demonstrate a higher risk of breast cancer associated with HT. Nevertheless, many patients and practitioners continue to be certain that taking HT will cause breast cancer.

Close to 60 observational studies of the association between HT and breast cancer have been published during the past 25 years, and no definitive answer exists because of inconsistency in the results of those studies. One analysis (prior to the WHI) of the evidence in those studies found that more than half of them reported either no difference in risk or a decrease in risk of breast cancer with ERT/HT use.27 The remainder of the studies reported only slight rises in breast cancer risk. Another group of researchers attempted to reanalyze more than 90% of the published data on breast cancer and HT use.28 They reported that postmenopausal women who had ever used HT had a small but statistically significant increase in risk for breast cancer compared with women who had never used HT. In women who were currently using HT or had recently used it, the relative risk rose by a factor of 1.02 to 1.04 for each year of use. After HT had been discontinued for 5 years, no significant excess risk remained. Also, breast cancers diagnosed in women who had used HT tended to be less advanced and were more localized.

Later reports from observational studies are also inconsistent. The report from the National Cancer Institute’s Breast Cancer Detection Demonstration Project was published in January 2000.29 These findings showed that the risk associated with recent HT use (both current use and use within the previous 4 years) was twice that associated with ERT. However, the relative risk for recent use of ERT was not statistically significant, and the difference between risks with ERT and HT was not tested for statistical significance. Right after that report was published, another group of investigators published and reported higher risk estimates for sequential HT regimens for 5 years or more of use than for continuous combined HT, although the difference was not statistically significant.30 In contrast to previous reports, this study found no difference in risk between current and past users.

At the end of 2000, the Nurses’ Health Study published its estimates of breast cancer risk associated with HT in postmenopausal women.31 The results were expressed as percentage increases in the cumulative risk of breast cancer and were frightening to many: The use of estrogen alone for 10 years was found to lead to a 23% increase by age 70 years, and the use of estrogen plus progestin for 10 years to a 67% increase by age 70 years. It is important for clinicians to realize (1) that the result is not an actual mathematical conclusion but the conclusion of the model—the consequences of a small difference in risk at the beginning that then is magnified as the math is carried out into the future—and (2) that risk estimates represent a projection, not an actual measurement.

One of the most disturbing reviews was published in 1998. Colditz32 summarized the evidence that endogenous estrogen and ERT not only increase the risk but are causally related to breast cancer. In his review of hormones and breast cancer, he included reports on cell proliferation and endogenous hormone levels as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer. He found evidence of a causal relationship between female hormones and breast cancer based on consistency, dose-response pattern, biological plausibility, temporality, strength of association, and coherence. He stated that the magnitude of the increase in breast cancer risk per year of hormone use is comparable with that associated with delaying menopause by a year. The fact that women who menstruate longer have a higher risk of breast cancer also provides support for a biological mechanism for the relationship between the use of exogenous hormones and increased risk. Colditz concluded that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous estrogens, and breast cancer incidence in postmenopausal women.

The WHI was the first randomized controlled trial confirming that conjugated equine estrogens combined with progestins do increase the incidence of breast cancer and the first to quantify the increase. The 26% higher risk of breast cancer occurred after about 4 years and translated to 8 more cases annually per 10,000 women.5 This is consistent with other epidemiologic data. The study was discontinued primarily because of the breast cancer incidence, which crossed the monitoring boundary for safety.

At the other end of the pendulum, investigations that have found no increased risk of breast cancer with HT or ERT use receive much less attention. The Iowa Women’s Health Study is prospectively following a cohort of women who were selected in 1985.33 After 6 years of monitoring, a statistically significant increase in the risk of breast cancer could not be detected in women who either had ever used or were currently using HT. Another report through 8 years of follow-up examined whether postmenopausal HT raised the risks for breast cancer and death from cancer in women with a family history of breast cancer.34 There was no significant increase in the rate of breast cancer even in women who had a family history of breast cancer and had been using HT longer than 5 years. These results are consistent with those of other reports that there is no additional risk in using HT/ERT for women who have a first-degree relative with breast cancer. My main criticism of these kinds of reports is that use of the words no significant increase is disturbing in that even a single additional case of breast cancer is significant. With a current incidence of one in nine, one more woman with breast cancer is one too many.

The latest analysis from the Iowa Women’s Health Study, an 11-year follow-up, showed an association between women who had ever used postmenopausal HT and the risk of breast cancers that were more localized and had a better prognosis.35 The researchers did not find an increased risk of invasive ductal or lobular carcinoma in women who had used HT either less than or more than 5 years. A slight increase in risk was observed in current users and users for less than 5 years; current users with more than 5 years of use had no increase in risk. These results are the opposite of those seen in the Nurses’ Health Study, that women who use HT for more than 5 years have a higher risk.36 Two other studies, the Carolina Breast Cancer Study37 and analyses from the National Health and Nutrition Examination Survey (NHANES),38 found no increase in risk with postmenopausal hormones. These later studies perpetuate the inconsistency in research on this issue that has been seen in the last 25 years. This pattern provides some logic to the point of view that if there is an increased risk of breast cancer associated with ERT/HT, the risk must be small, because by now, after so many years, we would have seen more consistency in the data, and the size of the risk estimates would be large rather than slight.

It is to be hoped that, in consultations with patients, clinicians can offer a balanced view, reassuring them that no studies find an increased risk of breast cancer with short-term use of HT and that the conflicting, inconsistent results of more than 60 studies shows that if there is an increased risk with long-term use, it is a small one. We can evaluate the benefits and risks for each patient and make our recommendations on a short-term basis, which can help each individual to make decisions that are not necessarily permanent. Research in this area of medicine is prolific, and if we keep up to date on the latest findings, we can inform our patients so that they can make informed, timely choices about their health care.

Cognitive Function

Observational studies have suggested that there is a relationship between endogenous estrogen exposure and cognition.39 A number of other observational reports have demonstrated that HT use may prevent or delay the onset or progression of Alzheimer’s disease, but additional observational results have been conflicting.40 A meta-analysis and systematic review was conducted in March of 2001 in which 29 studies were rated.41 In women who were symptomatic from menopause, postmenopausal use of estrogen improved verbal memory, vigilance, reasoning, and motor speed. There were no consistent effects on visual recall, working memory, complex attention, mental tracking, mental status, or verbal functions. Estrogen did not appear to enhance asymptomatic women’s performance consistently on formal cognitive testing. The meta-analysis did suggest that HT was associated with a lower risk of dementia, but the reviewers acknowledged that the studies analyzed had important methodology problems and information was inadequate to allow proper assessment of the effects of various estrogen preparations or doses, progestin use, and duration of use.

Studies in animals and the laboratory suggest plausible mechanisms for the potential of estrogen and the prevention and/or treatment of Alzheimer’s disease. Estrogen increases dendritic spine growth, axonal elongation, synapse formation, and neuronal survival. It also influences several neurotransmitters including acetylcholine, modulates nerve growth factor, increases apolipoprotein E, enhances blood flow, serves as an antioxidant, and enhances the uptake and metabolism of glucose. All of these effects could possibly inhibit the neurotoxicity of beta-amyloid and the damaging effects of free radicals, moderate the inflammatory events involved in plaque formation in the brain, enhance cerebral blood flow, and facilitate neuronal repair after brain injury.

Results of randomized trials of ERT and Alzheimer’s disease and the potential of estrogen for the treatment of this disorder have not been impressive in terms of benefits. In one study, estrogen replacement for 1 year did not slow disease progression or improve global, cognitive, or functional outcomes in women with mild to moderate Alzheimer’s disease.42 In another, participants at 10 of the 20 HERS centers were enrolled in the cognitive function substudy. The mean age of participants at the time of cognitive function testings was 71 ± 6 years. Among these older women with CAD, 4 years of treatment with conjugated equine estrogens plus progestins did not result in better cognitive function as measured on six different standardized tests.43

In the latest prospective study of dementia, prior use of HT was associated with reduced risk of Alzheimer’s disease, but duration of use very specifically affected the benefit; there was no apparent benefit from current use of HT unless the use exceeded 10 years.44

Ovarian Cancer

Evidence concerning a possible positive association between HT use and ovarian cancer risk is less consistent and of lesser significance than that for endometrial and breast cancers. Most of the data show a weak positive association. A large prospective cohort (observational) U.S. study of 211,581 postmenopausal women treated for longer than 10 years with conventional HT was associated with an increased risk of ovarian cancer.45 No distinction was made regarding type or regimen of HT or whether a progestogen was added to the ERT. Participants had no history of cancer, hysterectomy, or ovarian surgery. The study, monitoring women from 1982 to 1996, showed that women who were using HT at study entry had higher death rates from ovarian cancer than women who had never used HT. Risk was slightly but not significantly higher among former estrogen users. Women who used HT at baseline and for 10 years or more had a relative risk of 2.20, and former users with at least 10 years of use had a relative risk of 1.59. The annual age-adjusted cancer death rates from ovarian cancer per 100,000 women were 64.4 for baseline HT users with 10 or more years of use, 38.3 for former users with 10 or more years of use, and 26.4 for women who had never used HT.

In this observational study, as in the Nurses’ Health Study, the lack of information is almost more disturbing than the actual information. We have no data as to the type, dose, or combination of estrogen and progestogen used by the participants. As a result, many assumptions were made that influenced data analysis and the effect on relative risk. We know that the way in which hormones have been prescribed has changed from 1982 through 1996 and since then. In the early 1980s, most women were prescribed unopposed daily estrogen. During the 1980s, sequential estrogen plus progestogen therapy was introduced to eliminate the increased risk of endometrial cancer. Most women began to take 7 to 10 days of progestogen per month along with their estrogen. In the 1990s, common prescribing habits involved continuous and combined estrogen/progestogen regimens and lower doses of both hormones. Whether sequential or cyclic, progestogen is generally prescribed for at least 12 days per month. The number of different estrogens and progestogens has also significantly expanded and changed since the early 1980s and even in the last few years.

The investigators also reported on relative risk. Given the low incidence of ovarian cancer, even if there is a significant increase in relative risk, it may not have much of an impact on absolute risk. Although this study shows a doubling of the relative risk, the incidence of ovarian cancer mortality in postmenopausal women is extremely low, at 1.6%. It is also interesting to remember that 7 years or more of oral contraceptive use in reproductive-age women actually lowers the incidence of ovarian cancer.

A large, prospective study reported a significant twofold higher risk of ovarian cancer among long-term users of HT and ERT.46 A total of 44,241 postmenopausal women were selected from the Breast Cancer Detection Demonstration Project (BCDDP); 329 women who experienced ovarian cancer were identified. Women who used estrogen-only replacement therapy, especially for more than 10 years, were at significantly higher risk of ovarian cancer, with a relative risk of 1.8; women who used estrogen only for 20 or more years had a relative risk of 3.2. The good news was that women who used short-term combination replacement therapy were not at increased risk.

Focus on Estrogen Only

The WHI originally had three components: HT, a low-fat dietary modification, and supplementation with calcium and vitamin D. In addition, many of the women who did not qualify for the active treatments of the WHI became part of an observational group that was studied. Both arms of the placebo-controlled HT component (estrogen plus progestin [HT] and estrogen only [ERT]) were terminated before the planned ending date. The ERT arm of the WHI was halted on March 1, 2004, after 6.8 years of follow-up and less than a year before the planned closing date.24 The ERT arm was quite different from the HT arm in that the risks in the ERT arm did not exceed the benefits. The study showed a slightly increased risk of stroke, a decreased risk of hip fracture, a lack of increase in the risk of breast cancer and a possible reduction in breast cancer risk, and no effect on the incidence of CHD.

The key clinically relevant issues from the WHI ERT study are as follows:

The middle age group had about the same death rate in both the ERT and placebo groups, and there was a slightly higher death rate in the oldest age group.

What the WHI ERT study basically showed is that ERT, using CEE, is safe for most menopausal women who do not have a uterus. ERT reduced the risk of CHD in those women who started ERT near the age of menopause, it decreased the risk of fractures, it did not increase the risk of breast cancer, the risk of colorectal cancer was increased in women who started therapy at age 70 or older, and ERT was associated with a slight increase in the risk of stroke and VTE but there was no increase in death rates.

It would appear that use of ERT alone by women without a uterus is safer than using estrogen plus a progestin.

Natural Hormones

It is important to understand that most of the research on hormone regimens is on CEEs and MPA. However, that is not exclusively the case, and certainly some of the cardiovascular research has equally implicated 17-beta-estradiol (bioidentical estradiol). Nonetheless, in the most damaging data to date, from HERS I and II and the WHI, the hormones used were the equine estrogens and progestin. So, what we definitely know to be negative effects are associated with those regimens, and we do not in fact know whether the data can be applied to other regimens. It would be naive to dismiss the data and not to admit the possibility that the results would be the same. When hormones are determined to be appropriate or even necessary, however, it would at the very least seem logical to use the hormones we know not to be those with adverse effects.

Natural compounded estrogens and natural compounded progesterone, as well as natural testosterone and dehydroepiandrosterone (DHEA), such as those used by compounding natural pharmacies and the natural progesterone creams sold over the counter, are distinct and different in several critical ways from CEEs, conjugated plant estrogens, synthetic estrogens, and synthetic progestins. Natural hormones are made from either beta-sitosterol extracted from the soybean or from diosgenin extracted from Mexican wild yam root. Those compounds are then made into the desired hormone and are biochemically identical to the hormone the body produces. By definition, a natural hormone is plant-derived and bioidentical. The natural compounded estrogens are either estriol, estrone, or estradiol. Estriol is particularly unique because it has approximately one-fourth the potency of estradiol and estrone. Natural compounded estrogens are generally used in lower doses owing to the combined effect of the weaker estriol along with the estradiol and/or estrone. These natural estrogens are thought to be metabolized significantly differently by the body, have shorter half-lives, can be used in customized dosing regimens and potencies to fit each individual woman and clinical situation, and can be adjusted to be stronger or weaker in small units to taper someone off or onto hormones.

CEEs, those that were used in the WHI study, are quite different. In the 1970s it was believed that Premarin consisted only of 10 estrogens: 17-β-estradiol, 17-β-dihydroequilin, 17-β-dihydroequilenin, 17-α-dihydroequilin, 17-α-estradiol, estrone, equilin, 17-α-dihydroequilenin, Δ-8-9-dehydroestrone sulfate, and equilenin. Since then, advancements in technology have shown that the original 10 estrogens make up less than 40% of the hormonal content of Premarin. Through the use of modern analytic techniques, more than 200 individual components have been identified, including androgens and progestins.47 The composition of Premarin is complex, and different estrogens have various effects in different tissues. Herein may lie an explanation for problems with conjugated equine estrogens versus natural bioidentical estradiol, estrone, and estriol.

The steroid hormones, including the sex steroids produced by the ovaries, represent a subclass of lipids that share a four-ring steroid structure. The native compound from which all the sex steroids are derived is cholestane, the parent of cholesterol. When nutritional states of the individual and cell are normal, the principal precursor of steroid production is cholesterol in the plasma. The cholesterol enters the cells through a lipoprotein receptor system. The activity of the enzymes within the cells of that tissue determine the particular classes of steroids produced. Steroids, either endogenous or exogenous, enter the cells via passive diffusion. The tissues responsive to steroids have very specific intracellular receptors, each with a high affinity for its particular steroid. The primary action of the steroids is the binding of a steroid hormone to a receptor and the interactions of this receptor-hormone complex with the components of the cell. When the steroid binds, the steroid-receptor complex becomes activated and binds with very specific regions within the steroid-responsive regions of the genes. Most of the effects of steroids on responsive cells are mediated through the activation of very specific genes. The hypothesis is that a nonbioidentical hormone may act like a constant and indiscriminant environmental toxin to the genetic material within the cell because, even though it can bind to the receptor-hormone complex, it is a foreign substance.

Consider CEEs, which consist of more than 200 substances mostly foreign to a human. These substances, once ingested, are a part of that complex and therefore are activating those genes within the cell. Thus, there is a profound distinction between a hormone that is bioidentical to human hormones and one that is not. Beside the effect on the genes themselves, bioidentical hormones and nonbioidentical hormones may very well leave different metabolic footprints on the rest of the body, with different metabolic consequences. They may be directly cytotoxic to estrogen-sensitive tissues, alter binding of other hormones to those receptors, or change the liver’s metabolism of carcinogens. It is because of this distinction and the potential difference in metabolic consequences—as well as the shorter half-life of natural hormones—that naturopathic physicians prefer bioidentical natural hormones almost exclusively for the treatment of symptomatic menopause when hormones are required.

The distinctions between synthetic progestins and progesterone are even clearer. Natural progesterone has been studied and shown to have less adverse effects on the cardiovascular system than synthetic progestins such as MPA. Specifically, natural progesterone lowers HDL-C significantly less than MPA, is less atherogenic, and does not cause coronary artery spasm, whereas MPA does.

Natural estradiol may not be without concerns about its effects on the cardiovascular system and breast. However, it is typically used in a half-strength dose (0.5 mg total daily) because it is combined with the significantly weaker estriol. Estriol has been shown to have some ability to act as an antiestrogen in the breast and no significant effect on the cardiovascular system.

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