Selective Estrogen Receptor Modulators. Antonio Cano

Chapter 14. The Role of SERMs in the Management of Postmenopausal Women

• Joaquim Calaf i Alsina

14.1

Introduction

Menopause is biological evidence of aging in women. The absence of menstruation is clinical evidence of the inability of individual females to reproduce. However, what seems to be bad news is in fact proof that individual women can protect themselves. The reproductive process in the female is a very demanding one, and, consequently, nature has provided a mechanism to interrupt reproductive activity when biologic structures giving support to pregnancy enter the aging process. Conversely, in the male, whose participation in reproduction is limited both in time and resources, such a limitative mechanism does not exist.

The interruption of menstrual activity is the consequence of the exhaustion of the follicular pool in the ovary. Thus follicular development and ovulation no longer occur, and, as a consequence, the theca-granulosa system as a functional unit secreting estrogens disappears. This leads to a progressive decrease in the circulating concentration of estrogens. Detectable levels after menopausal ovarian failure are the consequence of peripheral aromatization of androgenic precursors. Consequently, the degree of estrogen priming differs among individuals according to the importance of their androgenic metabolite secretion by the hiliar ovarian cells and/or the adrenal gland cells as well as the amount of aromatizing tissue, especially skin and fat, they have.

Estrogens are the most significant messengers in the coordination of the body’s adaptive changes necessary to establish and maintain pregnancy. Thus, in women the majority of tissue systems are endowed with either or both of the presently identified estrogen receptors, alfa and beta. As a consequence, the resetting of the estrogenic control established after menopause leads to changes in tissue status, resulting in some cases in a higher risk for disease, either local or systemic.

All these estrogen-dependent changes coincide in time with the biological process of aging taking place irrespective of gender. A common tendency among gynecologists has been to attribute the majority of problems occurring after menopause to the absence of estrogens. This is as fallacious as ignoring the importance of estrogen deprivation in the onset and development of several female health problems. Thus any postmenopausal woman’s healthcare provider must be mindful of the consequences of both aging and hypoestrogenemia.

The evident biological changes related to menopause elicit a feeling of vulnerability in women that makes them more receptive to measures aimed at detecting or preventing risk situations and, consequently, improving health status and life expectancy. This opens an “opportunity window” that must be used to enhance the introduction of a new lifestyle and reinforce the acceptance of pharmacological preventive measures when needed.

Counseling postmenopausal women entails the identification of individual threats and risks and the implementation of behavioral or pharmacological measures. In this paper we try to describe an analytical system for handling this process efficiently.

14.2

Identifying Troubles and Threats

For the clinician, the individual patient remains more important than the general framework. In the process of counseling postmenopausal women, an individual evaluation is mandatory. It is not unusual for some of the risk factors relevant for one disease to also have an impact on the incidence of other pathological processes. Frequently these changes are mediated by modifications in the synthesis, metabolization, or substitution of estrogen precursors or metabolites. This is clearly the case for obesity, diet, or smoking, where the production of precusor metabolites, their peripheral aromatization, and bioavailability through their binding to sex hormone binding globulin determines the final estrogenic priming. This situation leads to an increased risk of events as a result of the toxic and metabolic effects of some behavioral circumstances like smoking or sedentarism.

A thorough clinical evaluation with a systematic anamnesis and physical examination including body weight, height, waist/hip ratio, and blood pressure should precede any lab tests or instrumental examinations. In the process of detecting the “weak points” of a given woman, the application of specific risk scores can be of interest.

14.2.1

Cardiovascular Risk

Frequency and impact on mortality should be the major determinants when establishing priorities. Thus cardiovascular disease (CVD) must come first. Even if very irregular in its impact from country to country, CVD remains the leading killer of women in Europe, as is the case in most developed countries.

Different classification systems are available to estimate the individual risk of presenting a cardiovascular event in the next 10 years. One of the most frequently used is the Framingham score risk, for which there is also software available online (Third Report of the National Cholesterol Education Program 2002), but recently several organizations involved in cardiovascular care have produced guidelines to identify and manage these risk situations (Mosca 2004).

14.2.2

Menopausal Syndrome

Immediately after menopause vasomotor symptoms are the most relevant issues directely related to estrogen decrease. Frequently they appear in the year preceding the last menstrual period and as a consequence of the hormonal changes characterizing perimenopause. Hot flushes do not affect all postmenopausal women, and among those presenting the symptom the severity varies from severe to very light (Oldenhave et al. 1993; Dennerstein et al. 2002) (Fig. 14.1). The menopausal syndrome is closely related to estrogen deficiency and together with hot flushes includes changes in sleep quality, concentration and mood, and genitourinary complaints. There is no individual correlation between the presence and severity of some of the most representative symptoms (i.e., hot flushes) and circulating estradiol levels. Thus, being asymptomatic does not necessarily imply having a better estrogen priming; on the contrary, some women apparently able to produce a considerable amount of endogenous estrogens, as deduced from cervical mucus characteristics or endometrial thickness, complain of intense hot flushes.

If we consider the periods characterized by the higher prevalence of particular symptoms or threats as “opportunity windows” for specific treatments, the period preceding and immediately following the last menstrual period can be identified as “the symptomatic window”. The duration of this symptomatic period also has a very high interindividual variation, and even if the median is around 30 months after menopause, some women experience hot flushes well beyond their sixties. Vaginal dryness, if not treated, increases in incidence and severity over time, and vaginal tissue changes have their clinical expression in discomfort and pain during intercourse but also in urinary frequency and nocturia.

Fig. 14.1. Incidence of hot flushes immediately before, during, and after menopause stratified according to severity (redrawn from Oldenhave et al. 1993)

14.2.3

Osteoporosis

The individual ability to produce estrogens becomes more relevant when analyzing estrogen-dependent diseases like osteoporosis and breast cancer. The incidence of breast cancer and fracture are inversely related. Cauley’s data also illustrate this negative correlation (Cauley et al. 1996).

Osteoporosis, the second most important threat to postmenopausal women, cannot be restricted to a “have or have not” condition. Bone health must rather be perceived as a continuum from normal bone to clinical fracture through osteopenia, osteoporosis, and subclinical fracture. Bone loss is the consequence of an increase in bone turnover, which is regulated by estrogens. Hypoestrogenism favors uncoupled bone remodeling and, consequently, a decrease in bone density and quality. Clinical fractures are associated with a sevenfold increase in death risk (Cauley et al. 2000). Diagnosing fracture risk is difficult, and both risk scores and early densitometric screening by themselves have poor predictive values. Continuous evaluation, combining both tools, is probably the most efficient approach. The International Osteoporosis Foundation risk evaluation score can be used to determine early prescription of DEXA evaluation (International Osteoporosis Foundation online).

Fig. 14.2. Progressive appearance of clinical and subclinical consequences of hypoestro- genism and aging open different “opportunity windows” for intervention

Vertebral and hip fractures have a different chronological incidence. Vertebral fractures begin to increase significantly after 65 years of age, whereas hip fracture incidence increases only 10 years later (U.S. Preventive Task Force 2002). This explains why the different studies with substances aimed at preventing fractures have been focused on populations of different age segments depending on the main outcome being measured. Studies showing an ability to prevent vertebral fracture have included populations in or near their sixties, whereas those focused on hip fracture prevention included patients at least 80 years old. For this reason we can consider that, starting at around age 60, we can open the “osteoporotic window” and that this window will remain open in the future (Fig. 14.2).

14.2.4

Breast Cancer

Postmenopausal breast cancer is, in the majority of cases, estrogen receptor positive (ER+) and, consequently, an estrogen-dependent disease. Estrogen circulating concentrations and lifetime exposure to estrogens are the most predictive risk factors for ER+ breast cancer (Cauley et al 1999). Gail’s score is the criterion used in the United States to indicate the use of tamoxifen to reduce breast cancer incidence. However, its external validity, and thus applicability in European countries with different breast cancer incidences, remains to be elucidated. Gail’s model, based on age, duration of reproductive life, family history, and the number of previous breast biopsies, is the most commonly used tool to estimate 5-year predicted risk (Gail et al. 1989). Scores of 1.67% or higher are considered to reflect high risk. As stated earlier, women with osteoporosis are considered to be at lower risk for breast cancer; this was also observed in an analysis of breast cancer incidence in the placebo group of the MORE study (Cauley et al. 2001). However, this was not the case for the women enrolled in CORE, a study designed to evaluate the efficacy of an additional 4 years of therapy in preventing invasive breast cancer in women who participated in the MORE trial (Martino et al. 2004; Delmas et al. 2005). Baseline risk estimation based on Gail’s method was 1.94%, and consequently these osteoporotic women should have been considered to be at high risk. In fact, the breast cancer incidence in the placebo group was 5.4 cases per 1000 women years, slightly higher than the 4.4 reported for the age group by the American National Cancer Institute (Kikuchi et al. 1997). Since age is a relevant component of Gail’s score and being osteoporotic does not imply a lower risk of presenting breast cancer, we can also open, shortly after menopause, an “oncologic window” where the risk of having a breast cancer detected will increase with each passing year.

14.3

Intervention Tools

14.3.1

Lifestyle Optimization

The first step in establishing preventive interventions should be the implementation of adequate measures to correct any significant detected changes in lifestyle. The lifestyle changes with the greatest impact on health are ces- sation/avoidance of cigarette smoking, regular physical activity, a healthy diet low in inappropiate fats and high in calcium, and weight reduction or maintenance. Women can expect to live a third of their life after menopause. As stated above, the perimenopausal period, as any critical period in life, increases one’s willingness to initiate an improvement process to increase one’s health status and avoid disease. The task of the health counsellor is to take advantage of this susceptible status to positively modify lifestyle. Personalized recommendations must be at the frontline of health and life expectancy improvement measures; without such recommendations any pharmacological intervention will be less effective.

14.3.2

Hormone Therapy

Hormone therapy has proven highly effective in controlling the menopausal syndrome, especially severe hot flushes (MacLennan et al. 2004), even at doses significantly lower than those used until now (Speroff et al. 2000; Utian et al. 2001). Women’s Health Initiative studies found that hormone replacement therapy, when administered as a primary prevention intervention for CVD in older women, increases the risk of heart disease and breast cancer. Even if a protective effect on fracture and colon cancer was observed, the risk-benefit ratio led to a recommendation of this treatment only for the short-term relief of menopausal symptoms (Rossouw et al. 2002; Anderson et al. 2004). The role of early administration of ovarian hormones to young postmenopausal women in the prevention of cardiovascular disease or late dementia remains to be elucidated. However, a protective effect on bone and, eventually, on lipid profile cannot be ruled out when these treatments are administered to symptomatic women.

14.3.3

Cardioprotective Treatments

Pharmacological measures to reduce CV risk are based on the identification and treatment of vulnerable risk factors. Among them hypertension, abnormal lipid profile, and hypercoagulant situations are at the origin of the majority of coronary events and stroke. Statins, thiazides, angiotensin-converting enzyme inhibitors, beta blockers, aspirin, and warfarin have independently shown their ability to prevent CV events (Mosca et al. 2004). Whether the prescription and control of these treatments is the task of the general practitioner or the gynecologist will depend on the organization of the health system in each country.

14.3.4

Bone Resorption Inhibitors

Prevention of osteoporosis and fracture can be achieved through limiting the resorption-remodeling process. Four main families of products can be effective in controlling bone resorption: estrogens, SERMs, bisphosphonates, and calcitonin. Large, prospective randomized trials have proven the effectiveness of all four families in preventing vertebral fracture (Rossow et al. 2002; Anderson et al. 2004; Cummings et al. 1998; Ettinger et al. 1999; Harris et al. 1999). Only the studies on alendronate and risedronate showed their effectiveness in hip fracture prevention (Black et al. 2000; McClung et al. 2001). Although the effect of all these antiresorptives on bone mineral density (BMD) varies, their impact on vertebral fracture is similar. Given that reduced BMD increases the risk for fracture, the inference that an increase in BMD would be significantly associated with a vertebral fracture risk reduction has not been proven. Only a small proportion of risk reduction in fractures is explained by the increase in BMD (Delmas and Seeman 2004). As a consequence, the choice between the different antiresorptive alternatives must be established on the basis of their side effects and extrasqueletal benefits (Fig. 14.3).

Fig. 14.3. The different anti resorptive substances have different effects on densitometric bone mineral density but similar impact on vertebral fracture incidence based on :Chesnut et al. 2000; 2Ettinger et al. 1999; 3Harris et al. 1999; 4Reginster et al. 2000; 5Black et al. 2000; 6Cummings et al. 1998

14.3.5

Breast Cancer Risk

Any intervention diminishing the access of estrogens, either in time or in concentration, to the estrogen receptor in breast tissue can be expected to lower the future risk of presenting a breast cancer. Lifestyle interventions should include smoking cessation, weight reduction, and alcohol restriction (Manier et al. 2004). Hormonal treatment should be restricted to symptomatic women and at the lowest effective dose for the minimal necessary time. A large- scale prospective trial showed that in the United States breast cancer prevention could be achieved, in high-risk women, with the administration of tamoxifen for not more than 5 years (Fisher et al. 1998). Prospective studies conducted in Europe did not yield the same results, probably as a consequence of differences in population selection or study design (Cuzick et al. 2003). The efficiency of raloxifene as a breast cancer preventive tool is under evaluation in a “face-to- face” study with tamoxifen (Wickerman 2003). Ongoing studies will provide information on the value of aromatase inhibitors in the prevention of breast cancer in high-risk postmenopausal women (Cuzick 2003).

14.4

Adressing Health Expectancy Improvement

14.4.1

Poly Approach and Multitasking

Diseases are frequently multifactorial, especially those involved in the aging process. Also, the aging process itself is not the consequence of a single disease but rather of progressive impairment in multiple organs or systems. Thus a disease must frequently be approached with the simultaneous administration of several drugs and measures, and to maintain well-being we must address more than one threat. These are the basis of the “poly approach” concept and help elucidate the search for “multitasking” products.

Lifestyle interventions share the concepts of poly approach and multitasking, targeting a multifactorial disease through different pathways and with an intervention having an impact on the outcome of more than one disease. A clear example of this is physical activity. It has been shown effective in decreasing cardiovascular risk, improving bone health, and decreasing breast cancer risk (i.e., multitasking) but at the same time is only one of the lifestyle interventions necessary to improve cardiovascular prognosis together with smoking, diet, or weight control (i.e., poly approach). Also, it has been suggested that diet can dramatically change cardiovascular risk (Franco et al. 2004). This explains why counseling about the implementation of adequate lifestyle measures must be the first step in any planned intervention for life expectancy in health improvement.

14.4.2

Pharmacological Poly Approach

Cardiovascular adverse events are prominent examples of a disease that occurs as the consequence of simultaneous multiple dysfunctions (hypertension, dyslipemia, clotting disturbances, etc.). Patients at high cardiovascular risk frequently receive an ACE inhibitor, a statin, and aspirin to normalize the parameters epidemiologically related to cardiovascular events as a primary or secondary preventive measure. This has engendered the idea of improving compliance by pooling inside a single capsule up to six substances (statin, aspirin, folic acid, tiazide, ACE inhibitor, and beta blocker) in what has been known as the “poly pill”. A mathematical calculation has allowed researchers to attribute to such intervention the ability to reduce cardiovascular disease by more than 80% (Wald and Law 2003) (Fig. 14.4).

Fig. 14.4. Concept of poly approach: several products are administered simultaneously to cover different aspects of the etiology of a given disease

The probability that such an approach will reach clinical application is low. There are examples of previous attempts to similar nonselective interventions, long-term aspirin being perhaps the most significant, that have both advantages and inconveniences, the latter being especially relevant in the low-risk subgroups (Collaborative Group of Primary Prevention Project 2001). General opinion favors the idea of a wise selection of an individualized choice of drugs and measures to cover the needs of a given woman (Mulrow and Kussmaul 2005).

14.4.3

Multitasking Drugs

The idea of concentrating more than one outcome in a single therapeutic approach opens the door to the concept of multitasking substances. Several body organs and systems share regulating mechanisms. Thus, the ability to influence the very early steps of these biological processes can lead to multiple and different consequences, either positive or negative, for the administration of a drug. The identification of these “multitasking” substances will mean a clear improvement in the efficiency of preventive interventions.

Recent evidences show that substances conventionally used in cardiovascular prevention or treatment also influence all causes of mortality (Hippisley- Cox and Coupland 2005). Statins have shown a potential protective effect on both osteoporosis (Renjmark et al. 2004) and breast cancer (Cauley et al. 2003; Brower 2003; Mueck et al. 2003), even if the results are not always reproduced (LaCroix et al. 2003) (Fig. 14.5). Also, aspirin is expected to have a positive influence on breast cancer risk (Garcia-Rodriguez and Gonzalez-Perez 2004; Tait 2004) and is currently being included in prospective breast cancer prevention trials together with aromatase inhibitors (Cuzick 2005). Consequently we are facing a new scenario where, with the same efficacy for the main outcome, the effects of multitasking drugs will be preferred to those showing only monotasking effects (Calabro and Yeh 2004).

Estrogens are genuine, naturally engineered multitasking substances aimed at adapting the female body to the changes necessary to cover needs related to becoming pregnant and maintaining health during pregnancy. Administered after menopause they have a proven multitasking activity (bone, colon, breast, etc.), even if negative consequences outweigh the benefits in the populations studied. These evidences help to explain a very complex and comprehensive regulating system based on the practically universal distribution of estrogen receptors. The ability to selectively modify estrogen action at the level of different organs could change the global index by avoiding estrogen stimulation where undesirable and mimicking estrogen action where suitable.

Fig. 14.5. Concept of multitasking: a single molecule influences evolution of different diseases through modulation of common pathway or information system

This profile fits perfectely the SERM concept. By designing molecules that exert specific effects on different organs and fine-tuning those molecules to a given woman’s advantage, we would be able to influence health and survival expectancies.

Much progress has been made in this field over the last four decades (Chle- bowski 2000). Tamoxifen is a substance able to block estrogen binding to estrogen receptors and, at the same time, itself induce protective effects on the breast and bone. It has, however, a negative estrogenic effect on thrombotic risk or endometrium cancer or by inducing hot flushes. It is now a first choice in preventive or adjuvant treatments in both pre- and postmenopausal women pending a final evaluation of the promising role of aromatase inhibitors.

Raloxifene represents a further step in the development of multitasking agents. The results obtained in large prospective studies have demonstrated a clear positive effect on bone density and prevention of vertebral fracture without any evidence of endometrial stimulation or cancer. A long-term study evaluating the effects of this substance on breast cancer risk among osteoporotic women has shown a sustained protective effect over 8 years of exposure (Martino et al. 2004), and a subanalysis of the MORE study has shown a significantly protective effect in a subgroup of high-cardiovascular-risk osteoporotic women (Barret-Connor et al. 2002). However, the ability to induce the appearance of hot flushes in recent postmenopausal women and the increase in the relative risk of venous thrombotic events remain negative aspects of this SERM.

New substances of this family are in development, and we cannot exclude the possibility that oriented modifications of the molecules of SERMs, statins, or prostaglandin inhibitors will be able to enhance their effect on the breast or bone, maintaining equivalent power in their genuine indication. Knowing that a perfect “multitasking” molecule is unlikely, we can expect to obtain the maximal benefit from a single pharmacological intervention with substances with relevant added positive effects.

14.5

Dynamic Decision-Making Diagram

Counseling a postmenopausal woman about improving her health and survival expectancies is a challenging task. Figure 14.6 represents a proposal for a decision-helping diagram. The main square framed by the two axes represents a given postmenopausal population from 50 to 80 years old. Fifty years is considered the average menopausal age, and the line before zero represents premenopause (note that on the abscissas the intervals are not in the same scale). On the ordinates the percentage of estimated women who might benefit from a given intervention is represented.

Healthy lifestyle is mandatory for all postmenopausal women together with adequate correction of detected risk factors. That is why this intervention is in the center of the diagram and concerns 100% of the women in this period. Then a decision must be made as to whether the woman’s risk profile calls for any intervention beyond lifestyle improvement. The use of surrogate markers or risk scores can be useful in evaluating individual patients.

Local treatment should be offered to all women, especially those not receiving hormone treatment. Urogenital atrophy and vaginal dryness is frequent, but women have difficulties in expressing these symptoms, which is why the clinician should address this issue systematically.

For cardiovascular risk detecting and correcting factors like hypertension, obesity, insulin resistance, and type 2 diabetes or abnormal lipid profile, according to preestablished guidelines, can dramatically diminish the number of events.

During the symptomatic window, beginning even before menopause, hormonal treatment remains the best alternative, administered at the adequate dose and for the necessary period of time. We must remember that WHI showed a significant increase in breast cancer risk only after 5 years of exposure in older women and at higher doses than those usually necessary to control symptoms. Also, hormonal treatment is not contraindicated in severely symptomatic women with cardiovascular risk as long as an adequate cotreatment for this condition is administered. The hormonal treatment should be progressively withdrawn when approaching 5 years of exposure.

Fig. 14.6. Dynamic decision-making diagram to position different alternatives in management of postmenopausal women (see text)

Regarding osteoporosis, the risk can change according to age, health status, and basal bone density or previous fracture detected. The alternatives for osteoporosis prevention and treatment can be divided according to their mechanism of action: those acting exclusively at the bone level, likebisphosphonates, strontium ranelate, or parathormone, or those modulating the normal bone remodeling regulatory system, closely related to estrogen priming, i.e., estrogens, SERMs, or calcitonin.

Women with osteoporosis, either densitometric or established, and some cases of osteopenia with increased fracture risk require pharmacological intervention. Any intervention for osteoporosis is expected to be long lasting. Thus it is difficult to expect that interventions in young postmenopausal women could be maintained for the remainder of one’s life. The susceptibility to side effects changes either with the process of aging or the repeated use of a given product. Sequential treatment schedules, adapted to the risk profile of each period, would probably be more suitable.

In the early to mid postmenopausal period, either after estrogen treatment or in asymptomatic women, SERMs, and specifically raloxifene, appear to be the best alternative. They are well tolerated, have shown efficacy on the kinds of vertebral fractures, that appear more frequently in this period, and act through the natural mechanism of the bone remodeling process, i.e., the estrogen receptor. The probability of inducing hot flushes decreases with time following menopause and makes the onset of this undesired side effect a rare event (Fig. 14.7). As an added value they have proven to decrease the risk of ER+ breast cancer. If ongoing studies prove a positive effect on cardiovascular risk, they will have the attributes of a true multitasking agent for this period (Wickerham 2003). Putting benefits and risks together results in a very positive risk-benefit ratio (Mullins 2003).

As aging progresses the risk of thromboembolism increases, as does the incidence of hip fracture. The severity of osteoporosis in this period requires a very active antiresorptive agent, even if it limits very actively the bone renewal process. At the same time, we do not expect a very long-term exposure that might hamper the gastrointestinal functioning. It is appropriate at this point to initiate or shift to a bisphosphonate that could be maintained as long as necessary. This substance will also be adequate whenever there is a contraindication for early use of SERMS such as venous thrombosis, administration of Hot Flash Incidence in Younger vs. Older Postmenopausal Women tamoxifen, or aromatase inhibitors in women with previous ER+ breast cancer or early symptomatic women not desiring hormonal treatment.

Fig. 14.7. Influence of raloxifen administration depends on age and time elapsed since menopause (redrawn from Davies et al. 1999 and Ettinger et al. 1999)

Finally, in very severe cases, the alternative to a bone remodeling agent such as teriparatide should be taken into consideration. The place for strontium ranelate, a substance without age-related contraindications, remains to be established as clinical experience in its use grows.

This is a proposal to help the clinician to counsel individual women. This process of individualization is crucial and is the best guarantee of a wise use of the different alternatives presently available for an efficient management of the postmenopausal period. Guidelines are only indications of the best choice for a majority of women, but, as health agents of our patients, we have the responsibility of determining how suitable they are for a given woman and introduce the appropriate corrections. In this context SERMs are an early alternative for osteoporosis prevention and treatment that provide an additive protective effect on the breast and are neutral on cardiovascular risk.

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