The risk-benefit analysis of hormone replacement therapy in the menopause

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Chapter 25 The risk-benefit analysis of hormone replacement therapy in the menopause

Tatijana Nikishina and Tim Hillard

The hormone replacement therapy (HRT) risk-benefit profile has been the subject of considerable analysis over the past decade and has been at the center of the debate that has polarized opinion between those who advocate the use of HRT and those who oppose it. Whilst there is broad agreement around some of the key benefits of HRT there is considerable difference about the interpretation of the risks in taking it. Recent revised data from the Women’s Health Initiative (WHI) and other randomized clinical trials since the publication of WHI together with various authoritative position statements have helped to clarify some of the uncertainties and provide more robust evidence for clinical decision-making.

The available evidence suggests that HRT 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]. However an individualized and rational approach to commencing HRT is important, as the risk-benefit balance will differ for each woman. There is currently less evidence for the widespread use of HRT for long-term chronic disease prevention [13], although again the balance between potential benefits and risks will differ from individual to individual.

There are a number of factors which can influence an individual’s risk-benefit ratio (Table 25.1).

Table 25.1. 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 HRT (combined or estrogen only)

Dose of HRT preparation

Route of HRT administration

Length of HRT use

This chapter aims to review the current evidence for the benefits and risks of HRT as a guide to clinical decision-making.

Benefits of HRT

For young, healthy menopausal women (below the age of 60) with bothersome symptoms the benefits of HRT generally outweigh the risks. However the risk-benefit profile for a particular woman is not static, therefore regular clinical reviews are necessary.

We will briefly discuss the main known benefits of HRT; many of these are discussed in more detail elsewhere in the book.

Vasomotor symptoms

Vasomotor symptoms – often described as hot flashes and night sweats – affect 60–80% of menopausal women to some extent [4]. 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 5–10 years) [5].

A Cochrane review reported a 75% reduction in the frequency and an 87% reduction in severity of hot flashes in HRT users [4]. 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 HRT 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 HRT 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 [5].

Urogenital symptoms

The prevalence of vulvo-vaginal atrophy among postmenopausal women is around 27% [5].

Topical vaginal estrogen therapy provides effective symptom relief and improvement in the cytological composition and physiology of the vaginal epithelium [2, 4]. Vaginal estrogens are also effective in reducing the number of episodes of recurrent urinary tract infections in postmenopausal women.

Topical vaginal estrogens have minimal systemic absorption and are considered safe. They are not associated with the risks associated with HRT discussed later. Systemic HRT preparations offer no therapeutic advantages over low-dose local estrogens in the management of atrophic vaginitis in the menopause, indeed meta-analyses suggest that bladder symptoms such as sensory urgency respond better to topical rather than systemic preparations [4].

Thus for women with just urogenital atrophy and no other symptoms, there is no advantage in taking systemic HRT. Women taking topical vaginal estrogen preparations should be reassured of their safety and that there is no requirement to take additional progestogens.

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 HRT improves the superficial and sometimes deep dyspareunia associated with vulvo-vaginal atrophy in postmenopausal women [2, 4]. 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 [2, 4].

Mood and depression

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 [6]. Recent RCTs have shown significant beneficial associations between HRT and mood; 68–80% of women using estrogen-only HRT reported decreased mood symptoms, compared with only 20–22% of women using placebo [6].

Both estrogen-only and combined preparations improve depressive symptoms in menopause when compared with placebo. Use of HRT has also been associated with a significant improvement in sleep quality [4]. 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.

Osteoporosis and fractures

Declining estrogen levels in the menopause are strongly associated with bone density loss and osteoporotic fractures [4]. Hormone replacement therapy is effective in preventing bone loss and reducing the incidence of all osteoporotic fractures in the menopause [7]. A Cochrane review indicates a 30% reduction in osteoporotic fractures (hip, vertebrae and overall) among women taking estrogen-only or combined HRT compared with placebo [8].

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. Coincidentally, these particular groups of women are also the most likely to suffer from menopausal symptoms. Initiating HRT 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.

The protective effect of HRT 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 [8], emphasizing the importance of ongoing bone conservation strategies.

Degenerative arthritis

Estrogen has a regulatory role in the metabolism of cartilage [7]. In menopause, the decrease of estrogen levels is associated with thinning of intervertebral discs and osteoarthritic joint changes. Most of these changes occur in the first 5 years after the menopause [4].

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% CI 0.70–1.00) of arthroplasty than those in the placebo group [4]. These benefits, however, were not evident in the WHI continuous combined HRT arm. It seems likely that progestogens neutralize the chondroprotective actions of estrogen; further studies are necessary to explore this.


Estrogens play an important role in skin physiology. The hypoestrogenic 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% 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.


Estrogen receptors are widespread in 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 HRT on cognitive function depends on the woman’s age and timing of HRT initiation. Several studies have revealed cognitive benefits of HRT if commenced around the time of menopause, i.e., during a “critical therapeutic window” period. Early HRT initiators have demonstrated improved memory, stronger global cognition and executive function [6]. A recent observational study has shown a 30% reduction of Alzheimer’s disease risk in women who initiated HRT within 5 years of menopause and used it for 10 years [6]. Later HRT initiation, as in the WHI Study, does not appear to have the same positive effect, indeed may even have a negative effect.

Further well-designed trials are necessary to explore the neuro-protective effects of various HRT preparations and their potential use in prevention of neurodegenerative conditions.

Cardiovascular disease

Cardiovascular disease is the leading cause of death in women over 50 years of age worldwide. Considerable evidence suggests that atherosclerotic changes are delayed by estrogen – whether endogenous in the premenopause, or exogenous in the form of HRT after the onset of menopause.

Estrogens are associated with reduction in endothelial injury, as well as plaque formation through lowering total and LDL cholesterol and raising HDL cholesterol levels.

Observational studies have shown a 40% decrease in cardiovascular disease rates, as well as cardiovascular disease-related and all-cause mortality rates, in women who commenced HRT in early menopause vs. non-users [9]. A “critical therapeutic window” theory can be applied here as the cardio-protective effect was not observed in women starting HRT after the age of 60 (Table 25.2). A more recent 10-year randomized trial of women receiving HRT started early after menopause showed that the HRT group had a significantly reduced risk of mortality, heart failure and stroke compared with the untreated group [2].

Jan 31, 2017 | Posted by in GYNECOLOGY | Comments Off on The risk-benefit analysis of hormone replacement therapy in the menopause
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