Abstract
“Although the exact mechanisms behind menopausal symptoms are unclear … what is certain is that reducing plasma estrogen concentration at the time of the menopause is the cause.”
The simple answer to this question is – no it is not. However, postreproductive health and the risk–benefit balance of hormone replacement therapy (HRT) are far from simple, making an easy answer impossible. In our experience, the use of estrogen replacement for the management of menopausal symptoms is the most effective treatment available and for the recently menopausal population has additional significant benefits with respect to long-term health. This view is supported by the British Menopause Society and Women's Health Concern recommendations on hormone replacement therapy [1].
Menopausal symptoms are experienced by 70–85% of women with up to 20% experiencing significant symptoms. These comprise the classic triad of vasomotor symptoms, urogenital effects and mood disturbance, which typically last for 4–5 years but can persist for up to 15 years in some patients. Consequently, this represents a significant burden to women in their postreproductive years [2].
The mechanisms behind hot flushes and night sweats are poorly understood. The thermoregulatory zone seems to be narrower in those who experience symptoms but whether this is a centrally or peripherally driven change is unclear. However, the impact of these vasomotor disturbances is often sleep disturbance, leading to chronic fatigue and exacerbation of other menopausal symptoms and any pre-existing medical conditions [3].
The urogenital effects and the impact these have on urinary and sexual function are more clearly understood [4]. The action of estrogen within the genital tract is necessary for the maintenance of the vaginal mucosa and adequate vaginal lubrication. As estrogen levels drop the urogenital tract atrophies, tissue glycogen levels decrease and lubrication is lost leading to vaginal dryness, altered genital tract flora and dyspareunia [5,6]. As this process continues there is further loss of tissue bulk and pelvic floor tone that can lead to dysuria, urinary urgency and an increased risk of urinary tract infections. The combination of the atrophic process, reduced libido and possibly decreasing testosterone levels make sexual dysfunction a common menopausal concern [7].
Although the exact mechanisms behind menopausal symptoms are unclear, particularly for vasomotor symptoms, what is certain is that reducing plasma estrogen concentration at the time of the menopause is the cause. As such it seems logical to replace what has been lost and so consequently hormone replacement must be the answer [8]. While progesterone may be needed for the protection of the endometrial lining – either as part of a combined HRT preparation or through a levonorgestrel intra-uterine system, it is the estrogen replacement that is the key to symptom relief. This can be provided as an oral or a topical preparation – the major advantage of the topical route is that it avoids first pass metabolism and often provides a more steady estrogen concentration that better mimics normal physiology.
Should we try to avoid estrogen replacement?
Unfortunately, estrogen replacement is accompanied by a degree of risk and the decision whether to take hormone replacement has to be tailored to each individual, taking into account the risks and benefits while accepting that for some patients there are clear contraindications (breast cancer, endometrial cancer or hyperplasia, high venous thromboembolic risk, unstable ischemic heart disease, cerebrovascular disease and active liver disease). The discussion of risks can seem daunting for patients and misrepresentation of current research within the media contributes to the uncertainty and confusion patients often feel when making this important decision. It is our responsibility, as healthcare professionals, to explain the known mechanisms behind menopausal symptoms and the clear benefits of estrogen replacement to provide patients with a frame of reference within which to consider the risks.
In the short term, there is likely to be a small increased risk of venous thromboembolism, cerebrovascular accident and gallbladder disease; and in the long term an increased risk of breast cancer and possibly cardiovascular disease [1]. These risks must be explained in context. For instance; the risk of venous thromboembolism (VTE) doubles with oral estrogen replacement but with a background risk of about 2 in 1000 risk of VTE in women at the age of 50 the overall risk remains low [9]. In this situation, it is important to recognize additional risk factors such as immobility, obesity and thrombophilia and consider the use of topical estrogen replacement as there are limited data to show that this lowers the VTE risk.
“While it is possible … to treat menopausal symptoms without estrogen; hormone replacement is a better quality, more physiological and a more effective and reliable solution to symptom control.”
Another aspect of the HRT discussion is ensuring the nature of the menopausal symptoms is clearly defined and the most bothersome symptom is acknowledged. For instance, if a patient has only urogenital symptoms or has persistent urogenital symptoms despite adequate vasomotor symptom control with a low dose systemic preparation, then local estrogen replacement can be invaluable. It is a highly effective treatment for urogenital atrophy and can have a positive effect on urinary symptoms and pelvic floor dysfunction. However, very little estrogen is absorbed systemically such that it can be safely used long term without endometrial protection and in some patients with a history of breast cancer [10]. The use of vaginal lubricants should also be explored as they can give significant symptom relief in some patients with urogenital symptoms and are particularly useful for patients with sexual dysfunction and genital tract symptoms resulting from intercourse [5].
Cardiovascular risk and the damaging results of the Women's Health Initiative Trial have been highlighted again recently with the publication of Cochrane Systematic Review on ‘Hormone therapy for preventing cardiovascular disease in postmenopausal women’ [11]. While the data show there is no overall benefit to taking hormone replacement for primary and secondary prevention of cardiovascular disease, the review does not address fully the question as to what the cardiovascular implications are for those patients taking HRT in the medium term between the ages of 50 and 60 years – in other words, the population most prescribers are considering. The subgroup analysis on those patients taking HRT in this early ‘window of opportunity’ showed reduced mortality and reduced incidence of cardiovascular disease such that “for every 1000 women taking HRT six lives were saved and eight cases of heart disease were prevented at a cost of five extra blood clots” [12]. Because the authors omitted this encouraging message in their published conclusions most of the media published the small increase in cardiovascular disease in all age groups as a bad news story. Interpretation of these large population studies on the use of hormone replacement must be done with care and any interpretations published responsibly to prevent confusion among patients and healthcare providers alike.
Estrogen replacement is highly effective at minimizing bone loss and preventing osteoporosis. For patients that are planning to take estrogen replacement for menopausal symptom control, this additional benefit of bone protection is good news. If there are contraindications to estrogen replacement, then there are alternative bone loss prevention strategies such as bisphosphonates. However, the question as to whether estrogen replacement is the answer in those patients with no menopausal symptoms but needing bone protection is open to debate and is likely to change significantly with patient age [13].
Are there alternatives to estrogen replacement we should consider?
For the management of hypoestrogenic menopausal symptoms, nonhormonal therapies should be considered when estrogen is contraindicated or poorly tolerated rather than being considered first line. Selective serotonin uptake inhibitors, serotonin-noradrenaline reuptake inhibitors, clonidine and gabapentin have all been explored and shown to be moderately effective in randomized controlled trials [7]. The results of these trials are difficult to interpret as they have mixed methodologies, are of a relatively short duration and there is a significant placebo effect on the reduction of hot flushes. For many women even a short duration of relief of symptoms means these treatment options are useful for some and should be offered to women who wish to avoid estrogen replacement.
The use of nonpharmacological treatment methods is common with 50–75% of women using vitamins and herbal therapies to treat symptoms. Unfortunately the industry regulation of such products means there can be significant variation in the amount of active ingredient in the products. When the effectiveness of such agents has been explored, the results have not been clear. Phytoestrogens within soy products have a greater effect than placebo in some trials but not in others. Other phytoestrogen containing preparations – red clover (Trifolium pretense) and black cohosh (Cimicifuga racemosa) have also been shown to be partially effective for treating hot flushes [14]. However, when considering all of these preparations we must remember that these are simply a way of providing weak estrogen replacement to patients and add further weight to the conclusion that estrogen replacement is the answer to menopausal symptoms.
As with most aspects of medicine, there is a fine balance between risk and benefits that means there is not a ‘one size fits all’ solution for all menopausal patients. While it is possible, when required, to treat menopausal symptoms without estrogen; hormone replacement is a better quality, more physiological and a more effective and reliable solution to symptom control.
Footnotes
EP Morris received speaker's fees and honoraria from Gedeon Richter, Abbott, Besins and Novo Nordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.