Summary

The average life expectancy is now over 80 years in most developed countries. Many more women have had oophorectomy, therefore the problems associated with menopause have become extremely important issues to the national healthcare planning and to insurance and pharmaceutical companies. Management includes medical and non-medical measures. In this article, the medical measures discussed include hormone replacement therapy (HRT), tibolone and raloxifene (a Selective Estrogen Receptor Modulator or SERM). Other non-HRT alternatives include phyto-oestrogens, androgens, bisphosphonates, calcitonin, calcium and vitamin D, statins, beta-blockers and angiotensin-converting enzyme inhibitors. The role played by some of these alternatives (e.g. phyto-oestrogens, androgens, bisphosphonates, and calcitonin) will be discussed in Part II in another article. Medication and lifestyle changes are both important for the high risk group.

摘要

由於大多數發達國家平均壽命巳超過80歲，而且每年有更多婦女進行卵巢切除手術，所以絕經期相關的問題，已成為國家保健計劃，保險公司和藥廠要處理的十分重要事項。治療分為藥物及非藥物治療。本文所討論的醫療方法包括激素替代療法(HRT)、替勃龍(tibolone)和雷洛昔芬(raloxifene，一種選擇性雌激素受體調節劑或稱SERM)。其他非激素替代療法類的藥物包括植物雌激素、雄激素、雙膦酸鹽類藥物、降鈣素、鈣和維生素D、他汀類藥物、-受體阻滯劑和血管緊張素轉換抑制劑。上述某些藥物（如植物雌激素、雄激素、雙膦酸鹽類藥物和降鈣素）的作用，將在第二部分中另文討論。對高危人群來說，使用藥物和改變生活方式都很重要。

---

Introduction

Climacteric is the period of life starting from the decline in ovarian activity until after the end of ovarian function. This includes peri-menopause, menopause and post-menopause. Menopause may be natural including premature ovarian failure (POF), or iatrogenic (e.g. surgery, chemotherapy or radiation).

Climacteric is considered to be a natural change of life which may be accompanied by various health consequences i.e., (a) menopausal symptoms (e.g. vasomotor or urogenital), (b) osteoporosis, (c) cardiovascular diseases (CVD) [including cerebrovascular diseases and coronary heart diseases (CHD)], or (d) Alzheimer's disease (which is more a problem associated with ageing and not unique to females).

Over one hundred years ago, the average life expectancy of the female was around 50 years of age. The problems associated with menopause were not the most important health concern in obstetrics and gynaecology. However, the average life expectancy is now over 80 years in most developed countries. It is estimated that in the USA alone, about 10 million women have had oophorectomy and about 300,000 more women undergo the procedure every year. Therefore, the problems associated with menopause are extremely important issues, to the national healthcare planning and budget, insurance industries, and pharmaceutical companies.

The prevalence and incidence of menopausal problems is difficult to assess as it varies in different countries, (e.g. it used to be believed that Asian women has less menopause problems than Westerners). However, the problems associated with menopause in Asia may increase due to longer life expectancy, cultural changes and lifestyle changes in the Asian community.

Management includes medical and non-medical measures. The non-medical measures include mainly lifestyle changes and public education of issues relating to the menopause, (e.g. education on smoking cessation, proper nutrition, exercise, moderate alcohol consumption). It is important to help females to understand the physiological and possible psychological changes that they may experience. It would minimize their fear of the unknown and alleviate worries over uncertain issues. However, this is not within the scope of this article and will not be detailed further.

In this article, the medical measures discussed include the use of hormone replacement therapy (HRT), tibolone or raloxifene (a Selective Estrogen Receptor Modulator or SERM). Other alternatives include phyto-oestrogens, androgens, selective oestrogen receptor modulators, bisphosphonates, calcitonin, calcium and vitamin D, statins, beta-blockers and angiotensin-converting enzyme inhibitors. Some of these will be discussed in Part II in another article.

Health issues of the menopause

(a) Menopausal symptoms

It is estimated that more than 1 million women will enter menopause each year. Some of them may experience hot flushes and other neuropsychological symptoms that may affect their quality of life. Vasomotor symptoms such as hot flushes and sweating are the symptoms that reflect the brain's response to hormonal changes during the climacteric, especially to fluctuating levels of oestradiol. The exact mechanism is still not absolutely certain. It is possibly related to the response of the thermo-regulation centre in the hypothalamus to physiological changes in the body. It usually gets better with time and patients should be reassured that, by itself, it does not impose any health threat and no medication is needed unless the symptoms are disturbing.

Menopausal symptoms may be associated with changes in sleep, mood, and other mental performance. All these associated symptoms should be evaluated separately and managed. Just as the Women's Health Initiative study (WHI) shows, there are risks associated with the use of HRT. The safety of even short-term use has raised concerns because there is no absolute "safe period". Although HRT remains the mainstay treatment for hot flushes, other nonhormonal treatments of the vasomotor symptoms such as clonidine, or serotonergic antidepressants should be discussed.¹

(b) Osteoporosis

During the first decade after menopause all women suffer an accelerating loss of bone. The importance of the increased loss of bone density is the high morbidity and mortality associated with the resulting spontaneous crushed fractures of vertebrae and fracturing of hips arising from an accidental fall or ordinary body movements. Osteoporosis causes substantial morbidity and mortality worldwide. It is estimated about $14 billion is spent on osteoporosis annually in health cost in the United States.

Measurement of bone mass by densitometry is the main diagnostic tool for osteoporosis. It appears that bone mineral density (BMD), especially in combination with age, predicts the risk of fractures in postmenopausal white women especially with regard to hip fracture. It appears that it is worthwhile measuring BMD in postmenopausal women over 65 years. For younger women, perhaps the use of risk factors may be used to select those at risk before requesting densitometry.²

This accelerated bone loss in postmenopausal women is precipitated by the deficiency of oestrogen. One possible reason to explain the rapid loss of bone mass is reduced effectiveness of ER-mediated processing of strain-related information by resident bone cells. At least one strain-related cascade responsible for adaptive control of bone architecture is mediated through oestrogen receptor (ER) alpha, the number and activity of which are regulated by oestrogen.³ The oestrogen deficiency increases the generation, life span, and activity of bone-resorbing osteoclasts. This continuous loss of bone density can be stopped by oestrogens and selective oestrogen receptor modulators (SERMs) or antiosteoclast agents such as bisphosphonates and calcitonin.

However, certain oestrogen analogues and bisphosphates may help bone growth by increasing the functional life span of the osteoblasts. But these agents have limited osteoblast stimulating or bone growth action as the unaffected osteoblasts fill in the holes that were dug by the now suppressed osteoclasts. They are antiresorptives but not bone anabolic agents. Calcium and vitamin D supplementation have few safety issues but have been shown to be ineffective, either as preventive or therapeutic options. Bisphosphonates are widely used and are effective anti-resorptive agents, though gastrointestinal tolerance is a possible side effect with some oral preparations. Intravenous administration may circumvent this, although this introduces the smaller problem of acute phase reactions. The side effects of HRT is well known after 40 years of use. Raloxifene (a SERM) appears to have a superior safety profile as compared to HRT and will be discussed in more details later.

The newest bone controllers include leptin from adipocytes and osteoblasts. Together with the statins, further research may give some promising results. (In fact, a new concept is developing suggesting that both atherosclerosis and osteoporosis share similar pathogenesis.) At the moment, the only known anabolic agents include the potent parathyroid hormone (PTH) and some of its 31- to 38-aminoacid fragments, which are either in or about to be in clinical trial or in the case of Forteo [hPTH-(1-34)] (Eli Lilly, USA) has just been approved by the Food and Drug Administration for osteoporosis and mending fractures.⁴

Cardiovascular and cerebrovascular diseases

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in menopausal women. It was thought that oestrogen deficiency and the associated dyslipidaemia after menopause are the causes. In vitro test suggests that there is a direct beneficial effect of ovarian hormones on the arterial endothelium. The reduction of oestrogen negatively influences the cardiovascular system. Therefore, the increased incidence of CVD observed in women after menopause should be considered on a multifactorial basis. Data available for the effects of ERT and HRT in the primary prevention of CVD are mainly observational. Meta-analysis of epidemiological studies showed that women who used oestrogens had a 34% overall reduction in the relative risk of cardiovascular events compared to the non-users. There are certainly limitations to these observational or epidemiological studies as many biases could affect the outcomes of the results. Most of the early epidemiological studies were using oestrogen only replacement therapy. The effects of oestrogen-progestin replacement therapy have not been adequately evaluated. However, subsequently much better randomized controlled trials (e.g. HERS study, WEST study, and the WHI study) all showed that the risks are not reduced by HRT. Instead, the risks are increased in the early period (1-5 years) of using HRT. Long-term use of HRT showed more risks than benefits (Women's Health Initiative Study).⁵ In none of the three age-groups studied (women in their 50s, 60s and 70s) was the cardioprotective effect of HRT confirmed. In all age groups, the HRT users had significantly more heart attacks, strokes, thrombo-embolism and breast cancers compared to those on placebo. The patients who took placebo however had more fractures and colonic cancer. Overall, the Global Risk Index is much higher in the HRT users. This means the risk with HRT are significantly more than the benefits gained. Therefore WHI HRT arm was prematurely stopped in mid-2002 (Women's Health Initiative Study).⁵

Management

(a) Hormone replacement therapy

Before the WHI study⁵ reports were released, there existed a constant dispute over the use of HRT. For example, observation studies had suggested the cardioprotective action of HRT. When the Heart and Estrogen/progestin Replacement Study (HERS), and its extension trial (HERS II) in postmenopausal women with CHD and an average age of 67 years was released, it showed that there was actually an increase of CHD in the initial period of its administration.

The HERS is a random control trial (RCT) of continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (MPA) against placebo, in 2763 women with a mean duration of 4 years follow-up. This study was neutral, with no reduction in CHD events or mortality. There were more events in the first year, and fewer in years 3-5. Even then, those favouring HRT still argued this did not apply to NORMAL menopausal women. Only when WHI study was released, then was the intrinsic weakness of the observational studies accepted.

The Women's Health Initiative (WHI) is a study designed to examine the effects of HRT on normal menopausal women. Ten clinical centres, out of a total of 40 throughout the United States, were selected as minority recruitment centres. Women enrolled in the study were followed up for a period of 8-12 years. The recruitment began in September 1993 and ended in December 1998. A total of 161,856 women participants 68,135 (18.5% minority) were included in the Clinical Trial (CT). Roughly half the patients were recruited for the two arms of the study, namely the use of conjugated equine oestrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg daily against placebo, and the conjugated equine oestrogen 0.625 mg daily only against placebo.

In May 2002, the HRT arm was prematurely terminated after an average follow-up of 5.2 years.⁵ The interim safety review found that the HRT increased the risk of invasive breast cancer,⁶ heart disease,⁷ stroke⁸ and pulmonary embolism. On the other hand, HRT reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks. Therefore the HRT arm was terminated as the Global Risk Index was too high for it to ethically continue.

This powerful RCT has revolutionized the concept of HRT from the earlier observational studies. The possible explanation was perhaps due to the intrinsic defects in observation studies (for example, selection biases). It is possible that the women using HRT in observational studies were healthier than those not using it. The WHI reported increased CHD events (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02-1.63). Stroke incidence but not mortality was significantly increased among HRT users in the meta-analysis and the WHI. The meta-analysis indicated that risk was significantly elevated for thrombo-embolic stroke (RR, 1.20; 95% CI, 1.01-1.40) but not subarachnoid or intracerebral stroke.Risk of venous thromboembolism among HRT users was increased overall (RR, 2.14; 95% CI, 1.64-2.81) and was highest during the first year of use (RR, 3.49; 95% CI, 2.33-5.59) according to a meta-analysis of 12 studies. Whether these findings related to women with menopausal symptoms and to different HRT regimens is unknown.⁹ Subsequently, the WHI Memory Study also showed that HRT did not only show no advantage in cognitive function, but that it significantly increased the probable dementia in HRT use compared with those taking placebo (HR=2.05, 95% CI=1.21-3.48).¹⁰

At the same time, a companion paper in the same journal reported an epidemiologic study with a mean of 13.4-years follow-up suggesting that oestrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer.

In February 2004, the ERT arm of the study was also prematurely terminated after an average follow-up of 6.8 years.¹¹ The interim safety review found that the ERT increased the risk of total cardiovascular disease (hazard ratio 1.39 with 95% confidence intervals [CI] 1.01-1.24) mainly due to the increased risk of stroke (hazard ratio 1.12 with 95% confidence intervals [CI] 1.10-1.39). On the other hand, ERT reduced total fractures (hazard ratio 0.70 with 95% confidence intervals [CI] 0.63-0.79) mainly due to the reduced hip fractures (hazard ratio 0.61 with 95% confidence intervals [CI] 0.41-0.91). There was no statistically significant change in the risks of CHD (hazard ratio 0.91 with 95% confidence intervals [CI] 0.75-1.12), total cancer (hazard ratio 0.93 with 95% confidence intervals [CI] 0.81-1.07), breast cancer (hazard ratio 0.77 with 95% confidence intervals [CI] 0.59-1.01), colorectal cancer (hazard ratio 1.08 with 95% confidence intervals [CI] 0.75-1.55), and pulmonary embolism (PE) (hazard ratio 1.34 with 95% confidence intervals [CI] 0.87-2.06). There was no significant effect on the total mortality (hazard ratio 1.04 with 95% confidence intervals [CI] 1.01-1.24) and global risk (hazard ratio 1.01 with 95% confidence intervals [CI] 0.91-1.12). The study was prematurely terminated because there was no actual advantage of using ERT.

Other than the risk of increasing endometrial cancer, whether HRT increases the risk of ovarian cancer is still a concern. A new paper based on the WHI study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion of an increase in the endometrial and ovarian cancer risk. The authors also conclude that, the increased workload of "endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen." Therefore, for patients given HRT, not only is there an increased risk of gynaecological cancer, the follow up and monitoring would also impose increased workload and requires increased health resources.

After the various reports from WHI^5-8 were released, the overall evidence indicates that HRT (i) does not confer cardiovascular or cognitive protection; (ii) increases breast cancer risk; (iii) increases stroke and CHD risks in the initial period of usage; and (iv) increased thrombo-embolic phenomenon and choelcystitis, (v) does not improve overall quality of life and (vi) increases probable dementia. HRT does, however, decrease fracture rates, vasomotor symptoms and colorectal cancer.

The ERT arm of the study also did not show any overall benefit of using ERT. Therefore, these kinds of information should be discussed carefully with the patients before either ERT or HRT is used.

However, despite the fact that everyone agrees that the WHI is a most well designed powerful study and it is unlikely any better study could be conducted in the near future, those favouring HRT still throw in arguments to defend the use of HRT.

At the end February 2003, a HRT manufacturer gathered some of the top international HRT experts to debate the results of the WHI study and discuss its possible implications for the future use of HRT. The WHI data were reviewed and summarized. Although it was generally agreed that the WHI study was well designed and executed, it was argued that the target population used in the WHI is not representative of target population for whom menopausal HRT is normally considered.

(b) Tibolone

Tibolone, like tamoxifen and raloxifene, and oestrogen (+/-progestogen) treatments prevent bone loss in postmenopausal women. Tibolone is inactive in itself and needs to be metabolized in the body before the metabolites extert their action. It was claimed that if tibolone is administered one year after menopause, this should not stimulate the endometrium and should not induce endometrial bleeding.

But there were subsequent reports of endometrial hyperplasia and carcinoma. It is also said to be helpful in reducing vasomotor symptoms. But unlike raloxifene, it does not possess antagonistic biological effects via the ER in breast against breast cancer. Tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective tissue oestrogenic activity regulators (STEARs).¹² However, unlike raloxifene and HRT, tibolone has not been studied adequately by any large scale prospective, double-blinded RCT.

(c) Selective oestrogen receptor modulators

Selective oestrogen receptors modulators include a group of drugs that is not derived from the natural sex steroid hormone. Therefore, it should not be regarded as "hormones" and the treatment should not be confused with HRT. However, they bind to oestrogen receptors just like oestrogens. Because of the variable structures, the drug-receptor complex may either function as an agonist (i.e., with effects similar to those imposed by oestrogen), or antagonist (opposite action).

Generally the SERM can be divided into 2 groups:

(A) Triphenylethylene derivative - e.g. clomiphene, tamoxifen and toremifene

(B) Benzothiophene derivative - e.g. raloxifene, droloxifene and idoxifene

Currently, only raloxifene is registered for use as treatment for osteoporosis and will be discussed here because it has been properly studied in the osteoporotic postmenopausal women. The most spoken, well-designed study so far is the Multiple Outcome of Raloxifene Evaluation (MORE) and this is mainly discussed here.

Both oestradiol and raloxifene bind at same site within the core of ER ligand-binding domain (LBD). But each has a distinct conformation shape in the transactivation domain of the LBD. This leads to different reactions with co-activators and co-repressors. The different reactions end in either an agonist or antagonist message on gene transcription. Finally the cells demonstrate either agonist or antagonist function. Raloxifene hydrochloride has antioestrogenic effects on breast and endometrial tissue and oestrogenic effects on bone, lipid metabolism, and blood clotting.

Cummings SR et al (1999)¹³ first reported the 3 year results of MORE, a multicenter, randomized and double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centres in 25 countries. A total of 7705 postmenopausal women were recruited. The mean age of 66.5 years old and all the women have osteoporosis (defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women). Ninety-six percents of the patients were Caucasians. Women who had a history of breast cancer or who were taking oestrogen were excluded. The patients were equally randomized to either taking raloxifene (60 mg, 2 tablets daily; or 60 mg, 1 tablet daily) or a placebo (1 or 2 tablets daily). In addition, all patients received supplemental calcium and cholecalciferol. Results showed that the incidence of breast cancers in those taking raloxifene (1 or 2 tablets daily) were significantly decreased when compared to the patients taking placebo {that is, thirteen cases of breast cancer among the 5129 women taking raloxifene against 27 among the 2576 women taking placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001)}. In other words, the risk of invasive breast cancer was decreased by 76% in the raloxifene group. To prevent 1 case of breast cancer, 126 women would need to be treated. The reduction is mainly due to the decreased oestrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), and not the oestrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Unlike HRT, raloxifene does not stimulate the endometrial thickness and there was no increase in endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). However, similar to HRT, the risk of venous thromboembolic events was increased (RR, 3.1; 95% CI, 1.5-6.2).

Cauley JA et al (2001)¹⁴ later reported the 4 years data and confirmed the protective effect of raloxifene against invasive breast cancer, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). This means that in order to prevent one case of invasive breast cancer, 93 osteoporotic women will have to be treated with raloxifene for 4 years. Again, the effect of Raloxifene is mainly on the reduction of oestrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30).

Presently, a head to head study is being carried out to investigate the effects of raloxifene and tamoxifen on breast cancer.¹⁵ If the results showed that raloxifene is as effective as tamoxifen in the management of breast cancers, then it becomes more logical to use raloxifene instead as this would not increase the risk of endometrial hyperplasia or cancer.

Ettinger B et al (1999)¹⁶ also reported the 3 years data from MORE study on bone. Bone mineral density was assessed annually by dual-energy x-ray absorptiometry. Vertebral fracture was determined radiographically at baseline and at 24- and 36-months follow-up. Non-vertebral fracture was ascertained by interview at 6-month-interim visits. At 36 months, compared with placebo, raloxifene significantly increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) (P<0.001). Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced irrespective of whether the women have a prevalent fracture or not. Risk of nonvertebral fracture in those receiving raloxifene showed a reducing trend though the data did not reach statistically significant level (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Women receiving raloxifene had increased risk of venous thrombo-embolism when compared to those taking placebo (RR, 3.1; 95% CI, 1.5-6.2).

Compared with HRT in the postmenopausal women, raloxifene not only does not increase the CHD or stroke during the initial period of usage, there also appears to be an overall trend of decrease in the stroke and CVD in the raloxifene users. However, this decrease is not statistically significant in the overall figures (possibly the events are too small in the overall population). The decrease is statistically significant only in the high risk group (as the incidence is higher). In this high risk group, the reduction of stroke is about 40% and the decrease in CVD is about 60%.¹⁷

Yaffe K et al (2001)¹⁸ also reported the effect of raloxifene on cognitive function. The mean scores of the groups on six tests of cognitive function, were assessed before administration of the tablets, at six months and one, two, and three years after the medication. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent.Overall there was no significant difference in the scores among the 3 groups. Being on raloxifene treatment for three years did not appear to affect the overall cognitive scores. The risk of decline in the cognitive function, appeared to be less in the combined raloxifene group on the two tests of verbal memory (relative risk, 0.77) and attention, (relative risk, 0.87), but the risk reduction did not reach statistically significant level when compared with the data from the placebo group. Newly reported or worsening hot flushes did not negatively influence test scores or the effect of treatment on test performance.

Conclusion

Menopause is an important event in a woman's life. To her, this represents an end to her hormonal and reproductive life. One would equate this as the start of ageing. Not only does she need to look after her bone status, her lipid profiles to minimize the CVD risks, regular screening against cancers, she also may need re-adjustment psychologically. As her physician, it is crucial that both the physical and psychological aspects are carefully assessed and appropriately adviced for a particular individual. It is also very important that the physician should be able to clarify different unfounded stories from the media. The mode of management should be proposed and not imposed. She should be given as much proven information as possible to facilitate her choice of decision.¹⁹

The problems which may develop after menopause are not limited to osteoporosis and bone fractures, therefore biphosponates, calcitonin, or parathyroid hormone alone may not be the first choice if the overall health of the woman is to be taken care of.

HRT was initially proposed and thought to be able to look after the women's menopausal health in general. The addition of a progestogen to the regimen of replacement therapy is important to protect the women from developing endometrial carcinoma in a woman who has an intact uterus. A number of studies suggests that progestogens may also have beneficial effects on bone metabolism. There is some controversy on which progestogen least attenuates the lipid benefits received from ERT treatment alone.²⁰ For example, medroxyprogesterone acetate (MPA) is one of the most commonly prescribed 21-carbon. However, it appears that MPA has a significant glucocorticoid (GC) activity and this may decrease bone density. It is thus proposed that progestogen with no GC activity may be a better choice.²¹ But in 2005, the WHI reports (and other RCT reports) showed that HRT had more harmful than beneficial effects and ERT had not shown any major global benefits.¹⁵

Raloxifene appears to be the first-line choice as this helps in osteoporosis, helps to induce favourable lipid profiles, seems to reduce breast cancer but risk-lifestyle improvement and changes are important too. The only possible major side effect is that of thrombo-embolism. Other minor side effects include hot flushes, leg cramps, more detection of endometrial polyp in the MORE study. In those who also suffer from hot flushes, careful counselling is needed to explain that hot flushes are not life or health threatening physically. The symptoms usually slowly disappear with time when the thermo-regulation centre in the hypothalamus has time to re-adjust. In those where the hot flushes are affecting the quality of life, a trial of clonidine or gabapentine is recommended.

In menopausal women, both osteoporosis and cardiovascular disease are major public health problems with increased morbidity and mortality. Not only are they associated with ageing, evidence now suggests that they may share similar pathophysiological mechanisms, e.g. dyslipidaemia, oxidative stress, inflammation, hyperhomocystinaemia, hypertension, and diabetes. The exciting possibilities of newer pharmacological agents (e.g. newer SERM with more positive beneficial actions on CVD and osteoporosis but less hot flushes), are promising. Much more research is necessary to investigate the relationship between these two common illnesses.²²

In the next few years, we should await eagerly to receive reports on the use of raloxifene in the management of breast cancer (compared with the use of tamoxifen)²³ and the use in CVD (the RUTH study).

In the future, we may be expecting more interesting reports of newer SERM {e.g. arzoxifene, [6-hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4- methoxyphenyl)] benzo[b]thiophene} in the prevention or treatment of breast cancer singly²⁴ or in combination with retinoids.²⁵

Other alternatives like phyto-oestrogens, androgens, calcitonin, calcium and vitamin D, parathyroid hormone and omega 3 will be discussed in Part II, in the next article.

Key messages

1. Oestrogen/HRT, clonidine or gabapentine can be tried to relieve the severe vasomotor symptoms. Short courses of oestrogen may help in women with serious urogenital symptoms. Psychiatrist's advice may be sought if the psychological symptoms are serious or worrying.
2. Raloxifene provides reasonable bone protection, favourable lipidaemia level, reduced cardiac attack and strokes especially in high risk patients. It also appears it has protective effects against breast cancer. ERT/HRT both show bone protection effect, but concern exists over the increased risk of breast cancer, initial risk of cardiac attack and strokes and the preliminary data suggesting possibly increased risk of dementia. Tibolone lacks support from powerful clinical RCT to be certain of its use and safety in long term.

---

---

References

 

Appendix: A simple comparison among HRT, ERT and raloxifene

MENOPAUSAL SYMPTOMS   HRT (mainly WHI study)   ERT ( mainly WHI study)   Raloxifene (MORE & CORE study) MINOR :             1. Vasomotor       2. Urogenital       ? MAJOR :             1. Osteoporosis       2. Lipids/CVD/CHD   Lipid profiles improved; no protection for CVD & CHD; CVD & CHD in 1st 5 years   Lipid profiles improved; no protection for CVD & CHD; stroke   Lipid profiles improve; general tendency CVD & CHD, only statistically significant in high risk women 3. Alzheimer's   No protection; dementia (?)   No protection; dementia (?)   No difference; no dementia SIGNIFICANT SIDE EFFECTS             1. TEM/PE         2. Breast pain       No 3. Breast cancer     ?   by 60-70% in 8 years 4. Uterine bleeding     Hysterectomised   No 5. Endometial cancer       6. Endometrial polyp   ?   ?   CVD=cardiovascular diseases; CHD=coronary heart diseases; ?=not certain