An Evidence-Based Future for Menopausal Hormone Therapy

“The data gathered over the past two decades have underpinned agreed guidance from key drug regulatory authorities, that: menopausal hormone therapy should be used for the short-term treatment of menopausal symptoms…”

Where have we come from?

In his book on the history of medicine, David Wootton notes that “…effective medicine could only begin when doctors began to count and to compare” [1]. The history of menopausal hormone therapy (MHT), defined as the use of estrogen(s), with or without progestagens (progestins), or related compounds, primarily for the treatment of the symptoms of the menopause [2], provides a clear example of the importance of using large-scale quantitative data to minimize the harms and maximize the benefits of medications [3].

MHT has been in clinical use since the mid-1920s. By the late 1960s estrogen-only products had become popular, particularly in the USA, primarily with the idea that they improved women's health generally and that they could counter the ‘defeminizing’ effects of the menopause [4]. Use of estrogen-only MHT dropped in the mid-1970s, following findings of a marked elevation in the risk of endometrial cancer and the use of combined estrogen–progestagen MHT, which did not increase endometrial cancer to the same extent, gradually increased. Many industrialized countries saw a rapid increase in MHT use during the 1980s and 1990s, largely due to the impression that it could improve quality of life and reduce the risk of disease in older women. By the late 1990s, around half of women aged 50–64 years in the UK had ever used MHT and one-third of women in this age group were current users [5] and conjugated equine estrogens were among the biggest selling pharmaceutical products in the USA. Although evidence was accruing, this very widespread use occurred in the context of major uncertainties about the risks and benefits of MHT. It was this uncertainty combined with widespread use that led to a global effort to provide reliable quantitative evidence on the risks and benefits of MHT, including the Women's Health Initiative Trials and the Million Women Study.

The estrogen–progestagen arm of the Women's Health Initiative Randomized Controlled Trial of MHT was stopped 3 years early, in 2002, due to evidence of increased the risks of serious disease in those randomized to take MHT, particularly breast cancer, and that these risks were not offset by beneficial effects on conditions such as hip fracture [6]. In 2003, the UK Million Women Study published results showing an increased risk of breast cancer in current users of MHT, compared with women who had never used it, with greater risks in users of estrogen–progestagen than in users of estrogen-only MHT [7].

Following publication of these results, use of MHT declined rapidly, accompanied by reductions in breast cancer incidence in a number of settings [8,9], consistent with evidence that MHT-associated risks are rapidly reversible after MHT use ceases [7,10]. For example, in the USA, a 66% reduction in MHT use was followed by a significant 11% reduction in breast cancer incidence from 2001 to 2004 among women aged 50 years or more, but not in younger women [9].

While the delay in the translation of research findings into clinical practice is often lamented, these immediate reductions in MHT use and in breast cancer incidence demonstrate that evidence can translate rapidly into more judicious, evidence-based prescribing, with documented reductions in harm, both for individuals and the population. However, use of MHT is still common, and strategies to minimize adverse outcomes, while maintaining selective access to MHT for those who are fully informed and in whom it is likely to have the best balance of risks and benefits, remain important. Key to this is ensuring that clinical practice is guided by the quantitative sum total of the appropriate evidence to date, and not overly influenced by the results of individual studies or subgroups [11].

The UK Medicines and Healthcare product Regulatory Authority Public Assessment Report on MHT [12] is the most recent independent quantitative review located; the overview below predominantly uses this, supplemented by data from other large scale studies.

Where are we now?

MHT is effective for the treatment for vasomotor symptoms (hot flushes/flashes, night sweats) and vaginal dryness/atrophy associated with the menopause [13]. For less specific symptoms that are often attributed to the menopause (e.g., irritability, mood swings), the efficacy of MHT is less established [14,15]. The risk of fracture is reduced among current versus never users of MHT [16,17] but this effect wears off rapidly following cessation of use, and risk returns to that of a woman who has never used MHT within 5 years after stopping [16]. Hence, to meaningfully impact on hip fracture risk through use of MHT, women generally need to be current users in their 70s and older, when hip fracture becomes a significant problem.

The risk of breast cancer is increased in current users of MHT compared with women who have never used it, with relative risks increasing with increasing duration of use. Risks are greater with the use of estrogen–progestagen than with estrogen-only MHT. Current users of estrogen-only MHT with around 5 years of use have a 20% increase in the relative risk of developing breast cancer; use for around 10 years leads to a 30% increase in risk [12]. Corresponding figures for estrogen–progestagen MHT are 60 and 120% [5,10,12]. The risk does not vary substantively according to the type of estrogen or progestagen and whether the MHT is administered orally or transdermally [12]. The risk of dying from breast cancer is elevated in women who are currently using MHT compared with never users [7,18] and use of MHT by women with a previous diagnosis of breast cancer increases the risk of recurrence [19].

In women with a uterus, the risk of endometrial cancer in current versus never users is increased around three-times with 5 years of use of estrogen-only MHT and nine-times with 10 years of use. Risks with estrogen–progestagen MHT where progestagens are added for 10 or more days per 28-day cycle do not differ significantly from those of women who have never used MHT. The risk of ovarian cancer is increased by around 20% among current users of estrogen-only and estrogen–progestagen MHT, and increases with increasing duration of use [12,20].

There is no significant effect, beneficial or adverse, of MHT on coronary heart disease and the UK Public Assessment Report found no effect on colorectal cancer [12]. The risk of stroke is increased by around 30% in current users of estrogen–progestagen and estrogen-only MHT, compared with women who have never used MHT [12]. The risk of venous thromboembolism is increased in current users of oral MHT, with a 30% increase in risk among women using oral estrogen-only MHT and a 130% increase in risk among those using oral estrogen–progestagen MHT [12]. Risks are greater in the first 2 years after starting use than in subsequent years [21]. Risk does not appear to be significantly elevated in women using transdermal estrogen-only MHT versus those who have never used MHT [21,22]; there are insufficient data on transdermal estrogen–progestagen MHT for firm conclusions to be reached [21]. Venous thromboembolism risks are greater for women using medroxyprogesterone acetate than for those using norethisterone or norgestrel as progestogens [21].

“An evidence-based future for menopausal hormone therapy incorporates high-quality clinical practice, based on up-to-date quantitative evidence on risk and benefits, in partnership with an informed and involved patient.”

The current evidence is that the MHT-associated risks identified here generally wear off within a few years of ceasing use [7,10,12].

When the major potentially life threatening conditions affected by MHT are considered together quantitatively – in terms of increases in breast cancer, stroke, ovarian cancer, venous thromboembolism and endometrial cancer incidence (estrogen-only MHT in women with a uterus) [12,16,23] and reductions in hip fracture – the overall harm is greater than the benefits, for both estrogen-only and estrogen–progestagen MHT [12]. However, the net adverse effects of estrogen–progestagen MHT are greater than those for estrogen-only MHT. For example, 5 years of estrogen-only MHT in European women aged 50–59 years without a uterus, leads to 0.5% of users experiencing an net excess of cases of breast cancer, ovarian cancer, endometrial cancer, venous thrombosis, cardiovascular disease that is not outweighed by hip fracture and colorectal cancer cases prevented; the corresponding figures are 0.9% for estrogen-only for women with a uterus and 1.4% for women using estrogen–progestagen MHT (with or without a uterus) [12]. Although these absolute percentages do not seem large, it should be borne in mind that the background incidence of breast cancer in European women is around ten per 1000 women aged 50–59 years over a 5-year period [12].

Women and their health professionals face the difficult task of weighing up the severity of their menopausal symptoms against the risk of serious disease attributable to use of MHT. MHT effects on nonlife threatening conditions such as increased risk of incontinence [24] and gallbladder disease [25,26] and reduced peripheral fractures [17] should also be considered.

What does an evidence-based future for MHT look like?

An evidence-based future for MHT incorporates high-quality clinical practice, based on up-to-date quantitative evidence on risk and benefits, in partnership with an informed and involved patient. This means moving away from older clinical ‘rules of thumb’ (e.g., previous assumptions that use of MHT for 5 years was ‘safe’) toward more specific consideration of the evidence. The data gathered over the past two decades have underpinned agreed guidance from key drug regulatory authorities, including the US FDA [27], the UK Medicines and Healthcare Products Regulatory Agency [12], the Australian Therapeutic Goods Administration [28] that:

• MHT should be used for the short-term treatment of menopausal symptoms (e.g., hot flushes, night sweats, vaginal dryness) only;

• Women considering use of MHT should be informed of its risks and benefits;

• MHT should not be used for the prevention of disease, or (in Europe and Australia) as first line treatment for osteoporosis;

• MHT should be used for as short a period of time as possible and the need for continuing use should be reviewed six-monthly [28] or annually [12].

Beyond this, areas of future attention include closer consideration of the type and delivery of MHT to minimize risk [11]. For women who have had a hysterectomy and require treatment, estrogen-only MHT is the most appropriate in terms of minimizing risk. Use of estrogen–progestagen MHT leads to greater relative risks of breast cancer, ovarian cancer and venous thromboembolism than estrogen-only MHT, but leads to lesser or no increases in the risk of endometrial cancer for women with a uterus. Because the background incidence of breast cancer is around five-times higher than that of endometrial cancer, use of estrogen-only MHT is also likely to minimize excess potentially life-threatening adverse events in women with a uterus, compared with use of estrogen–progestagen MHT, for around 5 years for women with and without a uterus. In women with a uterus, more prolonged use carries substantially greater overall risks; the current estimates suggest that absolute excess risks with 10 years of use are similar for estrogen–progestagen and estrogen-only MHT. It should be noted that in many countries prescription of estrogen-only MHT to women with a uterus is not accepted clinical practice, due to issues with uterine bleeding, endometrial hyperplasia and cancer.

The current evidence also indicates that use of transdermal estrogen-only MHT is likely to minimize the risk of venous thrombosis, compared with oral MHT. There is also evidence that preparations containing medroxyprogesterone acetate carry greater risks of venous thromboembolism than norethisterone and norgestrel containing preparations.