Chapter 23 – The Risk–Benefit Analysis of Menopausal Hormone Therapy in the Menopause




Abstract




The menopausal hormone therapy (MHT) risk–benefit profile has been at the centre of the debate that polarizes opinion between those who advocate the use of MHT and those who oppose it even before the publication of the original Women‘s Health Initiative (WHI) study in 2001. Whilst there is broad agreement around some of the key benefits of MHT there remains considerable difference about the interpretation of the risks in taking it. Revised data from the WHI and other randomized clinical trials since the publication of WHI together with various recent authoritative international position statements and recommendations since the last edition have helped to clarify some of the uncertainties and provide more robust evidence for clinical decision-making.





Chapter 23 The Risk–Benefit Analysis of Menopausal Hormone Therapy in the Menopause


Elizabeth Stephenson and Tim Hillard


The menopausal hormone therapy (MHT) risk–benefit profile has been at the centre of the debate that polarizes opinion between those who advocate the use of MHT and those who oppose it even before the publication of the original Women’s Health Initiative (WHI) study in 2001. Whilst there is broad agreement around some of the key benefits of MHT there remains considerable difference about the interpretation of the risks in taking it. Revised data from the WHI and other randomized clinical trials since the publication of WHI together with various recent authoritative international position statements and recommendations since the last edition have helped to clarify some of the uncertainties and provide more robust evidence for clinical decision-making.


The available evidence suggests that MHT should be offered to well-informed peri- or early postmenopausal women to control moderate to severe menopausal symptoms, as the benefits outweigh the risks in otherwise healthy women in this age group [1, 2]. Whilst many women remain fearful of the risks of MHT, the revised findings of the WHI trial analyses and subsequent analyses such as the NICE (National Institute for Health and Care Excellence) guidelines should reassure healthy women who require symptom control [3]. Whilst there is currently less evidence for the widespread use of MHT for long-term chronic disease prevention, MHT is a proven effective treatment for the prevention of osteoporosis and appears to also reduce cardiovascular disease risk if started in the early postmenopause. An individualized and rational approach to commencing and continuing MHT is recommended, as the risk–benefit balance will differ for each woman and for any individual woman over time. A variety of factors can influence an individual’s risk–benefit ratio (Table 23.1). This chapter aims to review the current evidence for the benefits and risks of MHT as a guide to clinical decision-making.




Table 23.1 Factors influencing an individual’s risk–benefit ratio for hormone replacement therapy



















• Relevant personal or family history
• Lifestyle (weight, diet, exercise, smoking and alcohol use)
• Severity of menopausal symptoms
• Age and time of HRT initiation in relation to onset of menopause (‘critical therapeutic window’)
• Type of MHT (combined or estrogen only)
• Dose of MHT preparation
• Route of MHT administration and length of MHT use


Benefits of MHT


For young, healthy menopausal women (below the age of 60) with bothersome symptoms the benefits of MHT generally outweigh the risks. However the risk–benefit profile for a particular woman is not static, therefore regular clinical reviews are necessary. In their comprehensive review of menopause management NICE recommends that review should take place after commencing treatment for short-term menopausal symptoms at 3 months to assess efficacy and tolerability, and annual review thereafter unless there are clinical indications for earlier review. We will briefly discuss the main known benefits of MHT; many of these are discussed in more detail elsewhere in the book.



Vasomotor Symptoms


Vasomotor symptoms – often described as hot flushes or flashes and night sweats – affect 60–80 per cent of menopausal women to some extent. The severity of these symptoms peaks in the late perimenopause and early postmenopause, but there is a large individual and ethnic variation in their prevalence, severity, frequency and duration (mean of 7–10 years) and some women continue to experience them well into their sixties and beyond [4].


MHT remains the most effective treatment for vasomotor symptoms. A Cochrane review reported a 75 per cent reduction in the frequency and an 87 per cent reduction in severity of hot flushes in MHT users [5]. As these symptoms can be debilitating in a significant proportion of women, managing them effectively should have an important positive impact on their quality of life. Although this seems obvious, clear data on the benefits of MHT on quality of life are lacking, primarily because randomized placebo-controlled trials of symptomatic women are not considered ethical in many countries. The addition of progestogen to estrogen as part of MHT did not show any change in results. The lowest effective estrogen dose should be used and increasingly lower and lower doses have proven to be effective.


Whilst there is little doubt that MHT is the most effective treatment for vasomotor symptoms many clinicians have been wary of prescribing it and have instead been offering women alternatives such as anti-depressants and clonidine. Following their comprehensive review of the data NICE recommended that selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or clonidine should not be offered as first-line treatment for vasomotor symptoms alone [3].



Urogenital Symptoms


The symptoms of vulvo-vaginal atrophy (VVA) such as vaginal dryness, soreness, dyspaerunia, urinary frequency, urgency and nocturia are extremely common amongst postmenopausal women. Topical vaginal estrogen therapy provides effective symptom relief and improvement in the cytological composition and physiology of the vaginal epithelium. Vaginal estrogens are also effective in reducing the number of episodes of recurrent urinary tract infections in postmenopausal women [6].


As topical vaginal estrogens have minimal systemic absorption, they are considered safe and are not associated with the risks associated with MHT discussed later. Systemic MHT preparations offer no therapeutic advantages over low-dose local estrogens in the management of VVA, indeed meta-analyses suggest that bladder symptoms such as sensory urgency respond better to topical rather than systemic preparations. Women taking topical vaginal estrogen preparations should be reassured of their safety and that there is no requirement to take additional progestogens. Topical estrogens can be continued safely long term to maintain healthy vaginal function and to prevent symptom relapse, which frequently occurs if they are stopped. Because they have no significant systemic absorption they can also be considered in women where systemic MHT is contraindicated, e.g. breast cancer patients, although this is off-label and requires careful consideration.


Whilst women taking systemic MHT for other indications are likely to gain beneficial effects on VVA, for women with just symptoms of VVA and no other symptoms, there is no advantage in taking systemic MHT. Approximately 15–20 per cent of women taking systemic MHT may not get complete relief of their VVA symptoms and in these women topical estrogens can be used in addition to systemic MHT.



Female Sexual Function


Sexual dysfunction is common amongst postmenopausal women and its correction can lead to improved quality of life for women and their partners.


Systemic and topical MHT improves the superficial and sometimes deep dyspaerunia associated with VVA in postmenopausal women, which is often the first step to improve sexual function [6]. Vaginal lubricants and moisturizers can be added to topical estrogen or used alone to improve symptoms further. Restoring libido is altogether a more complex challenge. For some women correction of underlying menopausal symptoms and improvements in sleep and mood can all have a positive impact. The addition of testosterone therapy has been shown to improve sexual desire and satisfaction in surgically and naturally menopausal women, provided appropriate doses are used so androgenic and virilizing side effects do not occur. The use of transdermal testosterone for women both on and not on estrogen/progestin therapy in the short term is thought to be effective and not associated with serious complications when treating hypoactive sexual desire disorder [7].



Mood, Depression and Anxiety


Peri- and postmenopause are associated with an increase in mood and depressive disorders. Estrogen interacts with mood-regulating brain mechanisms through a number of neurotransmitters and the serotonin system. Randomized trials have shown significant beneficial associations between MHT and mood; 68–80 per cent of women using estrogen-only MHT reported decreased mood symptoms, compared with only 20–22 per cent of women using placebo [2]. In a double-blinded randomised controlled trial women taking placebo were 2.5 times more likely to have high depression scores than those on MHT. MHT and CBT (cognitive behavioural therapy) improve low mood for some women and MHT can and should be considered in women experiencing these symptoms [3]. For some women the additional progestogen can have a negative impact on these symptoms. This may vary with the type, dose and route of progestogen so careful selection of combination therapy is required. SSRIs do not appear to improve low mood in women who are not clinically depressed. MHT use is also associated with a significant improvement in sleep quality.



Osteoporosis and Fractures


The relationship between menopause, the decline in bone density and an increased risk of osteoporotic fractures is well established [2, 8]. Equally numerous studies, including the WHI, have shown that MHT is effective in preventing bone loss and reducing the incidence of all osteoporotic fractures even in low-risk women. A Cochrane review demonstrated a 30 per cent reduction in osteoporotic fractures (hip, vertebrae and overall) among women taking estrogen-only or combined MHT compared with placebo.


Thus hormone replacement therapy should be considered one of the first-line choices of therapy in postmenopausal women below the age of 60 with a significant fracture risk and for those women with premature ovarian insufficiency. Women taking MHT primarily for menopausal symptoms will also derive benefit. The protective effect of MHT on bone mineral density may remain for a variable length of time after cessation of therapy before an inevitable gradual decline in bone density occurs, emphasizing the importance of ongoing bone conservation strategies. Initiating MHT after the age of 60 for the sole purpose of osteoporosis prevention is not recommended as a first-line therapy although it may still be effective.



Degenerative Arthritis


Estrogen has a regulatory role in the metabolism of cartilage. Declining estrogen levels after menopause is associated with thinning of intervertebral discs and osteoarthritic joint changes. Most of these changes occur in the first 5 years after the menopause. Timely hormone replacement initiation can have a protective effect on intervertebral discs and articulated joint cartilage. In the WHI Study, women treated with estrogen alone had significantly lower rates (RR 0.84, 95 per cent CI 0.70–1.00) of arthroplasty than those in the placebo group. These benefits, however, were not evident in the WHI continuous combined MHT arm. It thus seems possible that progestogens may neutralize the chondro-protective actions of estrogen, although whether this varies with type of progestogen is not known [2].



Skin and Muscle Mass


Estrogens play an important role in skin physiology. The hypo-estrogenic state of the menopause accelerates age-related skin changes (thinning and dryness of the skin, increase in the number and depth of wrinkles, decrease in skin elasticity). Several randomized, double-blind, placebo-controlled trials have shown a 30 per cent increase in dermal thickness in postmenopausal women after 12 months of estrogen therapy, as well as an overall increase in collagen content and a decrease in facial wrinkling.


Sarcopenia, which is associated with declining estrogen levels after the menopause, is one of the major factors responsible for declining motor function and increased propensity to falls in the elderly. Whilst MHT may help improve muscle mass and strength, women should be encouraged to adopt an active lifestyle with regular weight-bearing exercise to help maintain a healthy musculoskeletal system.



Cognition


Estrogen receptors are widespread throughout the central and peripheral nervous systems and estrogens facilitate autonomic regulation and cognitive functions. Early untreated surgical menopause is associated with an increased incidence of dementia and other neurologic conditions.


The impact of MHT on cognitive function depends on the woman’s age and timing of MHT initiation [2]. Several studies have revealed cognitive benefits of MHT if commenced around the time of menopause, i.e. during a ‘critical therapeutic window’ period. Early MHT initiators have demonstrated improved memory, stronger global cognition and executive function. In an observational study there was a 30 per cent reduction of Alzheimer’s disease risk in women who initiated MHT within 5 years of menopause and used it for 10 years, but later MHT initiation, as in the WHI Study, does not appear to have the same positive effect, indeed may even have a negative effect. This view is also supported by a case control study in Finland, which found Alzheimer’s sufferers were slightly more likely to have used MHT.


Further well-designed trials are necessary to explore the neuro-protective effects of various MHT preparations and their potential use in prevention of neurodegenerative conditions but at this stage the impact of MHT on the risk of dementia is unclear [3].

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Sep 9, 2020 | Posted by in GYNECOLOGY | Comments Off on Chapter 23 – The Risk–Benefit Analysis of Menopausal Hormone Therapy in the Menopause
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