The demise of HRT? The long-term safety of hormone replacement therapy

The role of hormone replacement therapy (HRT) in the health of middle-aged women has come a full circle. HRT has been widely accepted as the treatment of choice for the management of menopausal symptoms. However, the Women's Health Initiative (WHI) and other recent randomised controlled trials have failed to confirm beliefs of other potential benefits in reducing the risk of coronary artery disease (CAD) and stroke. Indeed, early increases in cardiac event and stroke rate have been seen in women taking combination HRT. An increased risk of breast cancer diagnosis has also been confirmed in HRT users. The use of HRT now needs to be regarded as a short-term therapy for menopausal symptom management with treatment individualised for each woman.     

Acetaminophen safety and hepatotoxicity – where do we go from here?

The role of hormone replacement therapy (HRT) in the health of middle-aged women has come a full circle. HRT has been widely accepted as the treatment of choice for the management of menopausal symptoms. However, the Women’s Health Initiative (WHI) and other recent randomised controlled trials have failed to confirm beliefs of other potential benefits in reducing the risk of coronary artery disease (CAD) and stroke. Indeed, early increases in cardiac event and stroke rate have been seen in women taking combination HRT. An increased risk of breast cancer diagnosis has also been confirmed in HRT users. The use of HRT now needs to be regarded as a short-term therapy for menopausal symptom management with treatment individualised for each woman.     

Oral investigational drugs currently in phase I or phase II for the amelioration of menopausal symptoms

Introduction: Menopausal symptoms have a substantial effect on the quality of life of many women; hence, investigations for the amelioration of menopausal symptoms continue to be necessary. The two main approaches to the amelioration of symptoms are hormone therapy (HT) and non-hormonal therapy.

Areas covered: This review provides a background for understanding the types of menopausal symptoms and their underlying physiology. The early clinical development of natural estrogen (estetrol, E4), neurokinin 3 receptor (NK3R) antagonists, and other non-hormonal therapies are covered. The status and outcome of these novel treatment modalities are also discussed.

Expert opinion: The recent observation in the Women’s Health Initiative (WHI) trials that HT was not associated in the long-term with all-cause mortality, brings renewed interest in the development of new treatment modalities in postmenopausal women. Estetrol (E4), a native estrogen with selective action in tissues, is a potential next-generation HT with improved cardiovascular and breast safety. NK3R antagonists may become an interesting new modality for the amelioration of hot flushes in women with contraindications to estrogens.     

Use of postmenopausal hormone therapy since the Women's Health Initiative findings

PURPOSE: To assess how use of postmenopausal hormone therapy (PHT) has changed since the Women's Health Initiative (WHI) trial was halted early due to an excess risk of stroke and other adverse outcomes. To estimate whether use of alternative drugs to treat menopausal symptoms (e.g., selective serotonin reuptake inhibitors [SSRIs], soy) has increased. METHODS: Women were interviewed in the Slone Survey, a random-digit-dial (RDD) survey of current medication use in a representative national sample. Information was obtained on PHT including dose, route, and reason for use, and on use of alternative drugs to treat menopausal symptoms. There were 3853 women aged >or=50 years, interviewed from 1/2001 to 6/2004. RESULTS: The average weekly prevalence of PHT declined 57%, from 28% in the first half of 2002 to 12% in the first half of 2004. Use declined for conjugated estrogens (CE) and for other estrogens, taken either alone or with progestin. The decrease exceeded 50% in most strata of age, race, education, and region. The proportion of PHT users taking 0.3 mg CE did not change. Comparing prevalence in 2004 with prevalence in 2002, there was no material increase in use of black cohosh (2.0% in 2004) or soy (2.0%) and use of SSRIs was somewhat lower (8.9%). CONCLUSIONS: These population-based usage data demonstrate a large decline in PHT use among women of postmenopausal age. The proportion of CE users taking lower doses has not increased. On a population basis, millions fewer women are using PHT in 2004 than before the WHI results were published, but there has been no appreciable increase in use of alternative therapies for menopausal symptoms over the same period.     

回眸到静思——如何理性地看待绝经后妇女的激素治疗

2002年WHI（Women’s Health Initiative，妇女健康启动）的研究报告，无疑为全世界的HT（Hormone Therapy，激素治疗）扔下了一颗重磅炸弹。该研究结果显示，每日倍美力0．625mg加安宫黄体酮2．5mg，连续应用5．2年后，与安慰剂相比，卒中增加41％，心脏病发作增加29％，静脉血栓形成率加倍，总的心血管疾病增加22％，乳腺癌增加26％，髋关节骨折减少1／3，总的骨折减少24％，结直肠癌发生率减少37％，总死亡率无差异。     

Black cohosh (Cimicifuga racemosa) for menopausal symptoms: A systematic review of its efficacy.

Since conventional hormone replacement therapy has fallen out of favour, alternatives are being sought by many women. These therapies include herbal preparations such as black cohosh (Cimicifuga racemosa). The purpose of this update of a previous systematic review is to evaluate the clinical evidence for or against the efficacy of black cohosh in alleviating menopausal symptoms. Five computerized databases (Medline, Embase, Amed, Phytobase and Cochrane Library) were searched to identify all clinical data that provided evidence on the efficacy of C. racemosa. Bibliographies of the articles thus located were scanned for further relevant publications. Only double blind, randomized, clinical trials (RCTs) were included in the evaluation of efficacy. No language restrictions were imposed. Trials were excluded if they did not focus on menopausal problems, they included women suffering medically induced menopause, they did not use black cohosh monopreparations, or they did not use placebo or a standard drug treatment for the control group. Six studies with a total of 1112 peri- and post-menopausal women met our inclusion criteria. The evidence from these RCTs does not consistently demonstrate an effect of black cohosh on menopausal symptoms; a beneficial effect of black cohosh on peri-menopausal women cannot be excluded. The efficacy of black cohosh as a treatment for menopausal symptoms is uncertain and further rigorous trials seem warranted.     

The Women's Health Initiative Study: individualisation of hormone replacement therapy in a defined South African population

Objective The aim of this study was to investigate the impact of the Women's Health Initiative (WHI) study on the prescribing of hormone replacement therapy (HRT) in a defined South African population and to establish whether patient therapy was appropriately individualised as a result of the WHI study. Setting Claims data from a South African managed healthcare organisation. Method A retrospective drug utilisation review (DUR) was conducted to identify HRT‐related prescribing patterns in the defined study groups. This analysis included determining discontinuation and initiation rates for HRT during selected 6‐month periods. An investigation into patient demographics and prescribing patterns followed, whereby trends observed among patients either initiating or discontinuing HRT in the 6‐month period post‐WHI publication were contrasted with patients using HRT prior to publication of the WHI study. The prevalence of concomitant disease states among these subgroups was also assessed. Key findings The discontinuation rate for HRT following publication of the WHI study increased from 3.47% to 7.54%, while the initiation rate decreased from 15.34% to 9.10%. Patients initiating HRT post‐WHI publication were generally found to be in the younger menopausal age categories (40 to 49 years). These patients were more likely to have been initiated on HRT types other than those investigated in the WHI study and were at a higher risk for disease states for which HRT use is beneficial, such as osteoporosis. Patients discontinuing HRT post‐WHI publication were generally found to be in the older menopausal age categories (60 to 69 years), were more likely to have been combined HRT users (although not necessarily the type investigated in the WHI study), and were at a higher risk for disease states for which HRT use is considered harmful, such as diseases affecting the cardiovascular system. Conclusion It can be concluded that HRT was appropriately individualised according to recommendations based on the results of the WHI study in the defined populations of this study.     

Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.     

Smoking cessation in peri- and postmenopausal women: a review

A substantial portion of smokers are peri- or postmenopausal women. Cigarette smoking and menopause have overlapping negative health consequences and may act synergistically to contribute to worse health outcomes in this population. Little is known about issues specific to peri- and postmenopausal women attempting to quit smoking; however, it can be hypothesized that they face unique challenges in quitting smoking. Particularly, negative affect and vasomotor menopausal symptoms may make smoking cessation particularly challenging in this group of women. Peri- and postmenopausal women are also more prone to weight gain following smoking cessation, and concerns about postcessation weight gain may contribute to reduced motivation to quit smoking or to relapse to smoking. Recent evidence suggests that estrogen level may be positively associated with nicotine reward, which may aid in the smoking cessation efforts of postmenopausal women while possibly contributing to worse outcomes in perimenopausal women. Unfortunately, no known studies have compared premenopausal women with peri- or postmenopausal women on smoking cessation outcome variables. Studies in postmenopausal women indicate that hormone therapy (HT) use does not affect nicotine withdrawal, smoking cessation outcomes, or weight gain following smoking cessation; however, a lack of randomized trials limits the strength of these conclusions. Evidence of the effects of HT on mood following smoking cessation is conflicting. Further research is needed to identify the unique factors influencing smoking cessation in peri- and postmenopausal women and to develop and test interventions that target these variables in a way that improves cessation rates among this population.     

Meta‐analysis: do irritable bowel syndrome symptoms vary between men and women?

Background Studies suggest that sex and gender‐related differences exist in irritable bowel syndrome (IBS), but data is often conflicting. Aim To evaluate gender differences and the effect of menstrual cycle and menopausal status on IBS symptoms. Methods We performed a systematic review of MEDLINE to search for studies comparing IBS symptoms between gender, menstrual cycle phases and menopausal states in IBS and/or healthy individuals. We performed meta‐analyses to compare the relative risk (RR) of individual IBS symptoms between men and women. Results Twenty‐two studies measured gender differences in IBS symptoms. Women were more likely to report abdominal pain (RR = 1.12, 95% CI: 1.02, 1.22) and constipation‐related symptoms (RR = 1.12, 95% CI: 1.02, 1.23) than men (all P < 0.05). However, men with IBS were more likely to report diarrhoea‐related symptoms than women with IBS (RR = 0.84, 95% CI: 0.75, 0.94, P < 0.05). A systematic review of 13 studies demonstrated that both IBS and healthy women reported increased IBS symptoms during menses vs. other phases. There were insufficient data to determine the effect of menopause and hormone supplementation on IBS symptoms. Conclusions In the general and IBS populations, gender differences in IBS symptoms exist, although these differences are modest. Studies suggest that female sex hormones influence the severity of IBS symptoms, but more studies are needed.     

Treatment of menopausal symptoms post-Women's Health Initiative: refinement of existing treatments and development of new therapies

Menopause is a normal life transition for women. More than 80% of women experience some symptoms at menopause and > 25% of women in western countries seek treatment for a variety of symptoms that accompany this transition. In addition, there are certain chronic disease processes that accelerate after the menopausal transition. Hormone replacement therapy (HRT) with various combinations of oestrogen and progesterone compounds has been the mainstay of treatment for menopausal symptoms, as well as theoretical reduction in acceleration of certain chronic diseases after menopause. After the publication of the results of the Women's Health Initiative study in June 2002, the safety of HRT, as well as its effectiveness in decreasing various chronic diseases, was challenged. New formulations of hormone therapy, as well as new treatments, are evolving to aid the reduction of menopausal symptoms and long-term risks of common chronic disease processes that accelerate after the menopause.     

Life after the women's health initiative: evaluation of postmenopausal symptoms and use of alternative therapies after discontinuation of hormone therapy

STUDY OBJECTIVE: To determine the number of women who have menopausal symptoms after discontinuing hormone therapy, to determine how many of these women subsequently require nonhormonal alternatives to manage their symptoms, and to assess the effectiveness of those therapies. DESIGN: One-year retrospective study. SETTING: Department of Family Medicine outpatient clinic at a university medical center. PATIENTS: From 378 postmenopausal women who discontinued hormone therapy between August 1, 2002, and August 31, 2003, we randomly selected 78 using electronic medical records to provide a sample with a 95% confidence interval and a 10% margin of error. MEASUREMENTS AND MAIN RESULTS: Reasons why the women discontinued therapy and any nonhormonal alternative therapies that they may have used to manage subsequent menopausal symptoms were recorded. The primary investigator contacted the 78 women to complete a telephone survey. In most women, at least one menopausal symptom recurred. Vasomotor symptoms (hot flashes) were most common and occurred in 41 (53%) women. In addition, 59 (76%) women reported using nonhormonal alternative therapies, and 40 (68%) of this group deemed the alternatives helpful. CONCLUSION: We strongly believe that health care providers, including pharmacists, must continue to communicate with and educate women regarding treatment options for menopausal symptoms. Clinical pharmacists are ideally suited to contribute to ongoing research in this area.     

Conjugated estrogens combined with bazedoxifene: the first approved tissue selective estrogen complex therapy

Menopausal therapy with a tissue selective estrogen complex combines estrogens with a selective estrogen receptor modulator, with the goal of blending the desirable effects of estrogens on menopausal symptoms and bone with the tissue selective properties of a selective estrogen receptor modulator. The first tissue selective estrogen complex to receive regulatory approval is a combination of conjugated estrogens (CE) with bazedoxifene (BZA). Clinical trials with CE/BZA in postmenopausal women have shown improvement in vasomotor symptoms, vulvo-vaginal atrophy, and bone mineral density, without stimulation of the endometrium or breast tissue, with a generally favorable safety and tolerability profile. CE/BZA represents a new approach to the management of menopausal symptoms in women with a uterus.     

Treatment of menopausal symptoms post-Women’s Health Initiative: refinement of existing treatments and development of new therapies

Menopause is a normal life transition for women. More than 80% of women experience some symptoms at menopause and > 25% of women in western countries seek treatment for a variety of symptoms that accompany this transition. In addition, there are certain chronic disease processes that accelerate after the menopausal transition. Hormone replacement therapy (HRT) with various combinations of oestrogen and progesterone compounds has been the mainstay of treatment for menopausal symptoms, as well as theoretical reduction in acceleration of certain chronic diseases after menopause. After the publication of the results of the Women’s Health Initiative study in June 2002, the safety of HRT, as well as its effectiveness in decreasing various chronic diseases, was challenged. New formulations of hormone therapy, as well as new treatments, are evolving to aid the reduction of menopausal symptoms and long-term risks of common chronic disease processes that accelerate after the menopause.     

Hormone replacement therapy: I. A pharmacoeconomic appraisal of its therapeutic use in menopausal symptoms and urogenital estrogen deficiency

Menopause and the accompanying reduction in estrogen production may cause a number of symptoms in women which include hot flushes, sweating, mood and sleep disturbances, fatigue and urogenital dysfunction. The effectiveness of estrogen-based hormone replacement therapy (HRT) in ameliorating these symptoms, and in preventing long term sequelae such as osteoporosis, is well established. Comparative trials indicate that oral conjugated estrogens 0.625mg, oral ethinyl estradiol 0.02mg and transdermal estradiol 0.05mg have equivalent efficacy in relief of mild to moderate menopausal symptoms and prevention of bone mineral loss. Concomitant progestogen therapy is usually prescribed for women with intact uteri to protect against endometrial hyperplasia and carcinoma. The addition of progestogen maintains and may even enhance the bone-conserving effects of estrogen, and continuous regimens appear to reduce the incidence of irregular menses. Adverse reactions are predominantly local skin irritation with transdermal preparations (14% of patients) and systemic effects common to most forms of HRT including breast tenderness, flushing, headache and irregular bleeding, occurring in less than or equal to 2% of patients. Data concerning the effect of HRT on quality of life are limited, but most analyses have assigned utility values of 0.99 for mild and 0.95 for severe menopausal symptoms. However, recent clinical data suggest that these utility values may underestimate the impact of menopausal symptoms on quality of life. The cost benefit and cost effectiveness of HRT in the treatment of menopausal symptoms have not been fully researched, although preliminary results suggest that conjugated estrogens and transdermal estradiol compare well with alternative therapies such as veralipride and Chinese medicines. A Swedish study using a prevalence-based approach estimated that estriol treatment in all women with urinary incontinence aged greater than or equal to 65 years resulted in monetary savings compared with treating 20% of women. Cost-utility data indicated that the change in quality-adjusted life years (QALYs) with HRT was always positive, but the degree of change was determined by the baseline assumptions. Estimated changes in QALYs with HRT ranged from 0.006 for 5 years of treatment with unopposed estrogen in women with intact uteri, to 0.5 for 10 years of the same treatment in women with severe menopausal symptoms following hysterectomy. Compliance with HRT is suboptimal as 5 to 50% of women withdraw from therapy, thereby increasing costs per year of life saved.(ABSTRACT TRUNCATED AT 400 WORDS)     

How to judge the association of postmenopausal hormone therapy and the risk of breast cancer

The relevance of postmenopausal hormone therapy (HT) for breast cancer risk has been long debated, although it is one of the most important barriers for women to accept HT. Various opinions have been reported from recent randomized clinical trials and epidemiological studies. These unanswered questions include: whether HT has a positive impact on breast cancer; whether risks of therapy with unopposed estrogen and combined estrogen-progestin are different; and whether different types and routes of estrogen and progestogens, as well as the duration and cessation of HT use, have different impacts on this disorder. Recently, there has been some good news such as the following: the currently available data do not provide sufficient evidence to prove a causal relationship between postmenopausal HT and breast cancer; breast cancer in postmenopausal women using HT usually has better prognosis than that of nonusers. In conclusion, HT is still the most effective method of relieving climacteric symptoms for many postmenopausal women. However, a possible risk of breast cancer associated with long-term HT usage should not be ignored. With respect to prevention of breast cancer, regular evaluation of individual breast cancer susceptibility and close follow-up through mammography and/or breast sonography are necessary strategies for the safety of HT use.     

Use of hormonal contraceptives in perimenopause: A systematic review

Hormonal contraceptives have been used in perimenopausal women to manage a variety of symptoms and prevent unintended pregnancy. However, it is unclear what contraceptive regimen is best for these women. To evaluate hormonal contraceptive methods in women experiencing perimenopause using two prespecified outcomes: perimenopausal symptom management and long-term effects. A literature search of PubMed and EMBASE databases was performed (January 1990 to October 2021) using search terms “perimenopause” and “contraception.” Relevant full-text articles in English were included. Fifteen clinical articles were reviewed: Fourteen were internationally based, and one study was conducted in the United States. Nine articles evaluated symptom resolution, and six of these nine reported statistically significant changes in favor of treating perimenopausal women with hormonal contraceptives compared with no treatment. Seven studies evaluated long-term outcomes including bone loss and metabolic parameters, and six of these seven showed statistically significant improvements with hormonal contraceptives. Based on limited data and a lack of comparative studies, the use of a levonorgestrel intrauterine device with supplemental low-dose menopausal estrogen has positive results for the management of disruptive perimenopausal symptoms and long-term outcomes. Hormonal contraception in perimenopausal women improves symptom management and long-term outcomes if patients do not have contraindications. When selecting a contraceptive for women in perimenopause, clinicians and pharmacists need to address specific patient risk factors, symptom profiles, long-term risks and benefits, and patient preferences.     

17Beta-estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman

Recent publications of the initial outcomes from the Women's Health Initiative (WHI) study of menopausal management have raised concerns over the safety of hormone therapy [1,2]. Every study, no matter how large or well conducted, has biases and limitations that preclude the ability to apply the outcomes to a larger group of individuals not specifically evaluated in the analysis. In particular, the hormonal arms of the WHI evaluated only a single dose of a daily oral regimen of conjugated equine oestrogen 0.625 mg [1,2], combined with medroxyprogesterone acetate 2.5 mg if the subject had a uterus [1]. The failure to evaluate non-oral regimens prevented the evaluation of hormone delivery systems that have been shown to provide similar symptom relief to oral regimens, but with a considerably different physiological impact. The once-weekly transdermal patch (Climara Pro releasing 17beta-estradiol 0.045 mg/day and levonorgestrel 0.015 mg/day has been shown to be highly effective in rapidly reducing the frequency and intensity of vasomotor symptoms and to significantly improve all categories in the quality of life Women's Health Questionnaire [3]. In addition, this transdermal combination system was not associated with any cases of endometrial hyperplasia, adverse impacts on cholesterol or lipid values and was associated with an increasing rate of amenorrhoea over time [3]. The 17beta-estradiol/levonorgestrel transdermal system is approved in the US for the treatment of moderate-to-severe vasomotor symptoms and the prevention and treatment of urogenital atrophy.