Hormone replacement therapy in menopausal women: Past problems and future possibilities

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-β, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.     

Hormone replacement therapy in menopausal women: Past problems and future possibilities.

Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-beta, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.     

Menopause-related symptoms: what are the background factors? A prospective population-based cohort study of Swedish women (The Women's Health in Lund Area study)

OBJECTIVE: The purpose of this study was to analyze the influence of sociodemographic characteristics and environmental factors on self-reported menopause-related symptoms among middle-aged Swedish women. STUDY DESIGN: Women who were born in the years 1935 to 1945 and who were living in the Lund area of southern Sweden were investigated. Each woman completed a generic questionnaire and underwent a personal interview that pertained to sociodemographic characteristics, lifestyle, and current health-related problems. With these background factors, the frequency and intensity of hot flushes and vaginal dryness were determined; risk factor analysis was evaluated with the use of the multiple regression models. RESULTS: There were 6917 participants, with a response rate of 64%. A lower risk for hot flushes was related to older age, high education, and vigorous physical exercise. The major risk factors for vasomotor complaints were current weight gain, part-time employment, oophorectomy, unhealthy lifestyle, and concomitant health problems. Light smoking, late age of menopause, higher education, and excessive weight reduced the risk of vaginal dryness. However, older age, marriage, and chronic diseases negatively affected vaginal complaints. The background factors had less impact on symptoms in women who used hormone replacement therapy. CONCLUSION: Sociodemographic characteristics, lifestyle, and concomitant health problems appear to be important modifiable determinants for menopause-related symptoms.     

Cytochrome gene polymorphisms, serum estrogens, and hot flushes in midlife women

OBJECTIVE: The purpose of this study was to evaluate whether genetic polymorphisms in selected cytochrome P450 enzymes (CYPc17alpha, CYP1A1, and CYP1B1), estradiol (E2) levels, and estrone levels were associated with hot flushes. METHODS: Women with hot flushes were those aged 45-54 years who reported ever experiencing hot flushes (n = 354). Women without hot flushes were those aged 45-54 years who reported never experiencing hot flushes (n = 258). Each participant completed a questionnaire and provided a blood sample for determination of genotypes, E2 levels, and estrone levels. RESULTS: Carriers of the CYP1B1 (Val432Leu) polymorphism were more likely to report having any hot flushes (risk ratio [RR] 1.16, 95% confidence interval (CI) 0.98-1.37) and at least weekly hot flushes (RR 1.29, 95% CI 0.98-1.70) than women without the polymorphism, although these associations were of borderline statistical significance. In addition, carriers of the CYP1B1 polymorphism were likely to have a statistically significant 30% increased risk of reporting moderate to severe hot flushes (RR 1.30, 95% CI 1.02-1.67) and a statistically significant 27% increased risk of reporting hot flushes lasting a year or more (RR 1.27, 95% CI 1.00-1.61) compared with women without the polymorphism. There were no associations between CYP1A1 or CYPc17alpha polymorphisms and hot flushes. Low E2 and estrone levels were associated with hot flushes, but they did not alter the association between the CYP1B1 polymorphism and hot flushes. CONCLUSION: These data suggest that a CYP1B1 polymorphism may be associated with severe and persistent hot flushes, independent of E2 and estrone levels.     

Endocrine and metabolic effects of simple hysterectomy

A survey of 60 women who had undergone simple hysterectomy with preservation of ovaries revealed a high prevalence of menopausal flushes. Only 5 (8%) had menopausal concentrations of gonadotropins and estradiol. This is similar to the prevalence of natural menopause in population of comparable age. Of the remaining 55 women, 28 (47% of the total) had normal gonadotrophins and estradiol concentrations although they complained of hot flushes; these levels were not significantly different from those in 27 women who did not flush. The "flushers" did, however, have significantly diminished bone mineral index and higher serum uric acid concentrations than the "non-flushers". Flushes disappeared in those women who took estrogen replacement therapy. These data show that although full-blown menopause does not increase in frequency following simple hysterectomy, a subtle diminution in estrogenisation is frequent. This hypo-estrogenisation is sufficient to cause: (a) hot flushes; (b) demineralisation of the skeleton and (c) an elevation in serum uric acid concentrations. There may be a case for estrogen therapy in all women who develop hot flushes following simple hysterectomy.     

Predictors of hot flushes in postmenopausal women who receive raloxifene therapy

OBJECTIVE: In a previous report, we described the results of a randomized, controlled trial that evaluated the potential of raloxifene to induce or exacerbate hot flushes. Here, we provide additional analyses that were undertaken to identify potential predictors of hot flushes and to assess the clinical usefulness of various therapeutic strategies for the reduction of hot flushes in postmenopausal women who receive raloxifene therapy. STUDY DESIGN: In this randomized, double-blind, placebo-controlled study, 487 unselected postmenopausal women were assigned randomly to receive treatment for 8 months with raloxifene, which was administered either at a dose of 60 mg/d every other day for 2 months followed by 60 mg/d (slow-dose escalation) or 60 mg/d throughout (raloxifene), or placebo. Data on the number, duration, intensity, and severity of hot flushes and awakenings because of night sweats were collected. Logistic regression models were used to examine the predictive value of various demographic and menopausal factors on the development or worsening of hot flushes. RESULTS: At baseline, 40.4% of all randomly assigned patients had hot flushes. The mean number of hot flushes (3-5 per week) was low. Fewer years postmenopause, surgical menopause, and previous estrogen or estrogen/progestin therapy were significant predictors of hot flushes at baseline but were not predictive of incident hot flushes during treatment with raloxifene. Of the women who received raloxifene therapy who had pre-existing hot flushes at baseline, 36% women had none at the end point. Early postmenopause and surgical menopause were significant predictors of a biologically relevant increase in hot flushes (>/=14 flushes/week). Early postmenopause, previous estrogen/progestin therapy, high body mass index, and greater duration of hot flushes at baseline were significant predictors of the need for symptomatic treatment. After 2 months of treatment, women in early postmenopause had significantly more hot flushes with raloxifene therapy than with slow-dose escalation ( P = .042), whereas there was no significant difference between raloxifene therapy and slow-dose escalation among women in later postmenopause. In the 50 patients who requested symptomatic treatment during the study, phytohormones or veralipride did not reduce the number of hot flushes markedly. CONCLUSION: A shorter time since menopause and surgical menopause are important predictors of hot flushes both before and during treatment with raloxifene. Previous estrogen/progestin therapy also increases the risk of hot flushes at baseline. For women in early postmenopause, slow-dose escalation of raloxifene therapy may be a suitable therapeutic strategy for the reduction of the risk of hot flushes.     

Red clover isoflavones and menopausal health

Menopausal symptoms such as hot flushes and night sweats can be very disrupting. While hormone replacement therapy is an effective therapy, concerns about side effects and breast cancer risk have stimulated interest into alternative therapies such as phytoestrogens. These are oestrogen-like compounds made by plants. Two major sources of phytoestrogens are soy and red clover. Data on randomised controlled trials of red clover for the control of menopausal symptoms are presented. The conflicting data are encouraging and suggest that phytoestrogens are a treatment modality that needs pursuing.     

Hot flushes, bone mineral density, and fractures in older postmenopausal women

OBJECTIVE: To assess whether greater severity of hot flushes is associated with bone loss or fracture risk in older postmenopausal women. METHODS: This study is a secondary analysis of 3,167 postmenopausal women in the Multiple Outcomes of Raloxifene Evaluation trial. Baseline hot flush severity was assessed by self-report. Femoral neck and lumbar spine bone density was assessed by dual-energy X-ray absorptiometry. Vertebral and nonvertebral fractures were determined radiographically and by interview. Baseline bone density, 3-year bone loss, baseline prevalent fractures, and 3-year fracture incidence were examined in women with varying hot flush severity. RESULTS: After adjusting for other characteristics, greater severity of hot flushes was associated with higher, rather than lower, baseline bone density (adjusted mean femoral neck bone density=0.633, 95% confidence interval [CI] 0.614-0.652 g/cm2, versus 0.611, 95% CI 0.608-0.613 g/cm2 for women with "severe" versus "minimal" hot flushes). Women with more severe hot flushes were less likely to have a baseline fracture (odds ratio 0.64, 95% CI 0.48-0.84, for vertebral fracture in women with moderate or severe versus minimal hot flushes). The 3-year annualized change in bone density did not differ among women with varying hot flush severity (P>.40 for all). Hot flush severity was not related to incident vertebral or nonvertebral fracture (P>.05 for all). CONCLUSION: Among osteoporotic women who are 5 or more years postmenopausal, greater severity of persistent hot flushes is not associated with progressive bone loss or risk of fracture, despite previous research linking hot flushes to bone loss during early menopause. LEVEL OF EVIDENCE: II.     

The contraceptive and hormonal requirements of the premenopausal woman: the years from forty to fifty

There is a growing awareness that many women over 40 require both contraceptive protection and hormonal replacement for the symptoms of the climacteric. These women are still menstruating and the risk of pregnancy remains, overshadowed by the increased life-threatening risk due to childbirth in this age group. The risk of mortality due to the use of oral contraceptives is little increased for the nonsmoking woman in the over 40 years compared with the years under 40. In contrast, women over 40 who smoke are best advised not to use hormonal contraceptives. It is evident from all the existing data that combination therapy is strongly advised if any replacement therapy is to be given a woman. There is considerable evidence suggesting that estrogen alone may be insufficient therapy and progestogen should be added to prevent endometrial hyperplasia, decrease the risk of breast cancer and prevent bone loss. In the premenopausal woman, such therapy should also provide contraception. Many physicians allow women 35 to 45 who do not smoke to continue on an oral contraceptive if there is no contraindication. However, a minimum-dose product has yet to be found close to the ideal of fulfilling both the contraceptive and therapeutic needs of women traversing a physiologically very hazardous period.     

Reproductive hormones and cancer: ovarian and colon cancer

Evidence continues to accumulate that oral contraceptive use provides substantial protection against ovarian cancer. Less clear is whether the benefit affects women with genetic predisposition or women in the perimenopausal age range. The role of hormone replacement therapy in the occurrence of ovarian cancer is unclear. Available evidence suggests that if there is any potential risk, it involves women who use estrogen alone. Few women if any entering the menopause are at risk. There is some evidence that oral contraceptives have a favorable impact on the risk of colorectal cancer. Available data are limited. Finally, there is growing evidence that hormone replacement therapy reduces risk of colorectal cancer, a benefit that accrues to perimenopausal women.     

Soy and red clover for mid-life and aging.

INTRODUCTION: Menopause is associated with mid-life, a time when many women begin to experience the signs and symptoms of aging, such as increases in blood pressure, changes in lipid profiles, loss of bone mass density, and diminished memory and cognition. Given the result of the Women's Health Initiative, many women no longer consider hormone therapy the first option for promoting healthy aging. Instead, they are turning to botanical and dietary supplement (BDS) products in place of hormone therapy. This paper reviews the evidence available for use of isoflavones from soy and red clover for the treatment or prevention of these health issues. METHODS: The MEDLINE and EMBASE databases were searched for articles relating to soy or red clover supplement use for prevention and/or treatment of heart disease, hyperlipidemia, osteoporosis, mood disorders and cognitive abilities. Studies were included if they were randomized, controlled trials and included peri- or postmenopausal women. RESULTS: Isoflavone products appear to be the most useful for improving lipid profiles; however, the evidence suggests that isoflavone extracts from soy are less effective than products containing soy protein or red clover isoflavones. Soy protein appears to reduce levels of total cholesterol and low density lipoprotein cholesterol, while red clover reduces levels of triglycerides and increases high density lipoprotein cholesterol. The data were somewhat less convincing, although promising, for increasing bone mass density and improving cognitive abilities. CONCLUSIONS: Research suggests that isoflavones found in soy foods and red clover appear to have a small but positive health effect on plasma lipid concentrations, bone mass density, and cognitive abilities. Given the lack of serious safety concerns in the short term, it would appear that including soy and red clover in the diet of postmenopausal women, not withstanding a soy allergy, might be beneficial.     

The pathophysiology of menopausal symptoms

Increasing life expectancy means that most Western women will experience the menopausal transition. This phase of reproductive life involves a biopsychosocial process where the majority of women experience physiological changes, influenced by a wide range of ethnic, psychological, social and cultural factors. With relatively similar endocrine changes, symptom reporting should be generalized, yet more women in Western cultures report vasomotor symptoms (hot flushes and night sweats) compared to women in Asian cultures. Different approaches to menopause based on biological/medical, psychological or psychosocial premises result in different treatments for women who have troublesome symptoms.Hormone replacement therapy (HRT) is widely used in the management of symptoms associated with oestrogen withdrawal (hot flushes, night sweats, sleep disturbance, vaginal dryness and dyspareunia), but has no known role in the treatment of midlife depression or arthritis. HRT prevents menopausal bone loss and osteoporotic fracture, though long-term use remains controversial because of the increased risk of breast cancer, myocardial infarction and stroke, as reported by the Women’s Health Initiative.     

Taking an integrated approach: managing women with phytoestrogens

An integrated approach can be employed when counselling women about menopausal management options, where lifestyle, complementary therapies and hormone replacement therapy (HRT) are discussed. Women might opt to use an alternative approach to HRT for a variety of reasons, e.g. fear of side-effects and risks or contraindications to HRT. There are many choices of dietary and herbal approaches for menopausal symptoms, which essentially divide into food supplements and herbal medicines. The choice can often be overwhelming and confusing for the woman. Of concern, the evidence for efficacy and safety of some of these complementary therapies can be extremely limited or non-existent. In order to enable women to make a fully informed choice, it is important that, when a recommendation is made regarding a specific complementary therapy, it should focus on preparations for which a significant dataset exists for efficacy and safety and in which there is ongoing research and development. One of the most extensively studied food supplements has been the phytoestrogenic preparation containing red clover isoflavones. There have been six randomized trials thus far studying the impact on vasomotor symptoms, three of which have shown a significant benefit compared to placebo. There are also data from small randomized and observational trials showing positive outcomes for surrogate markers of osteoporosis and cardiovascular disease. A recent study using validated depression scales has shown that women using red clover isoflavones may also derive psychological benefits. Safety data are reassuring for the endometrium and breast, although further studies would be welcome, particularly in women with significant medical risks.     

Menopausal hot flush: Is it only a nuisance or also a marker of cardiovascular disease risk?

Hot flush is one of the most commonly reported symptoms during menopause; however, it is not experienced by all menopausal women, for reasons that remain unclear. In this review, we present current evidence that link hot flushes with cardiovascular disease, suggesting that the persistence of hot flushes many years after the menopause may represent a marker of an underlying disorder that increases the risk for cardiovascular disease.     

Folic acid supplementation: The new dawn for postmenopausal women with hot flushes

Hot flushes, experienced by 75% of menopausal women, are associated with estrogen deprivation. Estrogen was shown to ameliorate hot flushes by interacting with monoamine neurotransmitters in the brain; reducing noradrenaline and increasing serotonin. Hormone replacement therapy (HRT), the first treatment option, causes concerns over possible increased risks particularly breast cancer. Folic acid is involved in the biosynthesis of serotonin and nordrenaline, which is responsible for its effects on mood and cognition, and degrees of folate inadequacy, not severe enough to produce megaloblastic anaemia, were found to be associated with depression and cognitive malfunctioning. Also, increased age was observed to relate to reduced serum and cerebrospinal fluid folic acid levels. There is emerging evidence that folic acid supplementation ameliorates hot flushes by the same mechanism as estrogen. To explore this hypothesis, a multi-centre, double-blind, placebo-controlled randomized is being set up to compare the effect of 5 mg folic acid vs placebo in reducing the frequency and severity of hot flushes in postmenopausal women, and on the blood level of serotonin and noradrenaline. If folic acid supplementation is demonstrated to be effective, this will be a turning point in the clinical practice since it represents a cheap, safe and well-tolerated alternative to HRT.     

Noradrenergic and serotonergic modulation to treat vasomotor symptoms

Hot flushes are a major clinical problem for many menopausal women. Their aetiology is unknown. Centrally acting neurotransmitters are involved, but this involvement is yet to be fully characterized. In clinical trials with optimal patient selection and compliance, estrogen can reduce the frequency of hot flushes by 70-80%, and placebo by 20-40%. For some women, however, there are contraindications to the use of estrogen, and others are unwilling to use it. Furthermore, hot flushes may persist in spite of adequate estrogen replacement, and to improve symptoms physicians then have either to add another drug to the regimen or find an alternative to estrogen. The most commonly used non-hormonal alternatives for climacteric symptoms are neurotransmitter modulators such as the selective serotonin reuptake inhibitors. These reduce the frequency of hot flushes by 60%. The mechanism of this effect appears to differ from that underlying their effect on mood. They are generally well tolerated and rates of adverse events are far lower than those reported in studies of the use of these agents for depression. The limited efficacy of clonidine suggests that adrenergic mechanisms may be involved and data are awaited for more specific selective noradrenaline reuptake inhibitors. Thus, non-hormonal treatments are not as effective as estrogens in relieving hot flushes but may have a place as an alternative.     

Menopause: evidence-based practice

Menopause is a physiologic transition and is assuming an increasing importance as the demographic bulge moves through this phase. The transition takes place over several years. It is characterized by depletion of the ovarian follicles, decreasing inhibin leading to increases in follicle-stimulating hormone and loss of the menstrual cycle, accompanied by decreased estradiol production and typical symptoms. The role of hormone therapy in menopause has shifted from preventive use to a limited role in symptom management, for which it remains the most effective intervention. There is good evidence from observational and randomized trials of an increased risk of breast cancer in women on estrogen plus a progestin, compared with those on estrogen alone. There are insufficient data to be able to determine if there are clinically important differences between various progestins and progesterone with respect to breast cancer risk, nor between different regimens. Even relatively short-term exposure to unopposed estrogen will increase the risk of atypical endometrial hyperplasia or cancer; women who have their uterus should be using a progestational agent. Lifestyle changes at menopause are important and effective for preventive health. Recent evidence suggests that the discordance between epidemiologic studies with respect to cardiovascular outcomes and the Women's Health Initiative randomized controlled trial (WHI RCT) data might be attributable in large part to the older age of women enrolled in the WHI.     

Long-term follow-up of acupuncture and hormone therapy on hot flushes in women with breast cancer: a prospective, randomized, controlled multicenter trial.

OBJECTIVE: To evaluate the effects of electro-acupuncture (EA) and hormone therapy (HT) on vasomotor symptoms in women with a history of breast cancer. METHODS: Forty-five women were randomized to EA (n = 27) for 12 weeks or HT (n = 18) for 24 months. The number of and distress caused by hot flushes were registered daily before, during and up to 24 months after start of treatment. RESULTS: In 19 women who completed 12 weeks of EA, the median number of hot flushes/24 h decreased from 9.6 (interquartile range (IQR) 6.6-9.9) at baseline to 4.3 (IQR 1.0-7.1) at 12 weeks of treatment (p < 0.001). At 12 months after start of treatment, 14 women with only the initial 12 weeks of EA had a median number of flushes/24 h of 4.9 (IQR 1.8-7.3), and at 24 months seven women with no other treatment than EA had 2.1 (IQR 1.6-2.8) flushes/24 h. Another five women had a decreased number of flushes after having additional EA. The 18 women with HT had a baseline median number of flushes/24 h of 6.6 (IQR 4.0-8.9), and 0.0 (IQR 0.0-1.6; p = 0.001) at 12 weeks. CONCLUSION: Electro-acupuncture is a possible treatment of vasomotor symptoms for women with breast cancer and should be further studied for this group of women.     

Bio-psycho-socio-cultural perspectives on menopause

The menopause transition is a bio-psycho-socio-cultural process. Recent prospective studies highlight the complex ways in which lifestyle and cultural factors influence women's experience of the menopause. For the majority of well women, the menopause is a relatively neutral event, although women living in Western countries in general report more symptoms than those from non-Western cultures. Hot flushes and night sweats are the main symptoms of the menopause, and while the exact physiological causes are unknown, the role of norepinephrine is implicated in lowering the threshold for flushing. Psychological factors - including anxiety, stress, thoughts and beliefs and self-esteem - influence the experience of hot flushes, and a cognitive behavioural model is described which is compatible with a bio-psycho-socio-cultural perspective. Relaxation and cognitive behavioural approaches appear to be acceptable to women, and there is some evidence for their efficacy, but larger controlled trials are needed.     

The pathophysiology of menopausal symptoms

Increasing life expectancy means that most Western women will experience the menopausal transition. This phase of reproductive life involves a biopsychosocial process where the majority of women experience physiological changes, influenced by a wide range of ethnic, psychological, social and cultural factors. With relatively similar endocrine changes, symptom reporting should be generalised, yet more women in Western cultures report vasomotor symptoms (hot flushes and night sweats) compared to women in Asian cultures. Different approaches to menopause based on biological, medical, psychological or psychosocial premises result in different treatments for women who have troublesome symptoms.Hormone Replacement Therapy (HRT) is widely used in the management of symptoms associated with oestrogen withdrawal such as hot flushes, night sweats, sleep disturbance, vaginal dryness and dyspareunia, but has no known role in the treatment of midlife depression or arthritis. HRT prevents menopausal bone loss and osteoporotic fracture, though long-term use remains controversial because of the increased risk of breast cancer, myocardial infarction and stroke, as reported by the Women's Health Initiative. An understanding of the pathophysiology of menopausal symptoms and the risks and benefits of both hormonal and non-hormonal treatments assists in the individual management of patients.