Menopausal hormone therapy

Menopausal hormone therapy: is there cause for concern?

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Although three-quarters of women experience menopausal symptoms, a subset of more than a third of women have moderate to severe symptoms that are frequently debilitating. Hallmark symptoms include hot flushes and night sweats that persist for about 40% of women into their 60s, disturbed sleep, anxiety and low mood, and vulvovaginal atrophy.

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 The negative effect of bothersome vasomotor symptoms on wellbeing is of the same order of magnitude as housing insecurity.

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 Furthermore, having any vasomotor symptoms more than doubles the likelihood of low self-reported work ability.

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 Postmenopausal oestrogen depletion results in bone loss, leading to osteoporosis and fracture risk.

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 Increased intra-abdominal fat and cardiometabolic changes with menopause predispose to cardiovascular disease, cancer, and dementia.

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Indisputably menopausal hormone therapy (MHT) alleviates symptoms and can profoundly improve quality of life.

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 Large randomised controlled trials have shown that MHT reduces fractures (even in the absence of osteoporosis), colon cancer, endometrial cancer, and diabetes risk, and that oestrogen-only MHT reduces cardiovascular disease events.

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 Randomised controlled trials have also shown increased venous thrombosis and gall bladder disease risk with oral oestrogen, and a small increase in breast cancer with oestrogen plus medroxyprogesterone acetate (MPA) or norethisterone (NETA). Hence MHT has shifted to predominantly non-oral oestradiol and, when indicated, progesterone or dydrogesterone.

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Against this background, a recent observational study from the Collaborative Group on Hormonal Factors in Breast Cancer

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 has triggered a global shockwave of fear among women that MHT causes breast cancer, similar to that generated previously by the sensational reporting of the first publication of the Women’s Health Initiative (WHI) study. The false perception that resulted from misreporting of the WHI findings led to thousands of women discontinuing or never commencing therapy. Australian data published in 2015 suggest that only about 11% of perimenopausal and postmenopausal women aged 40–65 years use MHT despite high symptom prevalence.

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 Is this fear justifiable? No.

Data from observational studies can be hypothesis generating but tend to overestimate treatment effects. Hence, randomised trials are essential to confirm or nullify their findings. Use of routinely collected health data without a priori research aims increases the chance of bias. Much of the data included in the recent Collaborative Group analysis

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 was collected during routine health delivery, or relied on participants recalling past treatment and duration of use. Specific characteristics of the included populations—nurses in the Nurses’ Health Study

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 or women attending a mammogram being invited to participate in a study of the breast effects of MHT in the Million Women Study

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—introduce bias. These two studies contributed almost half the included data.

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 Despite the investigators describing their work as worldwide epidemiological evidence, 67% of the prospective data were from two UK databases (unpublished routinely collected general practice health data and the Million Women Study)

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 and 24% were from the USA, with only one study from the southern hemisphere included.

With acknowledged limitations, analysis of the WHI trials suggested an increased breast cancer risk with conjugated oestrogen–MPA therapy (hazard ratio [HR] 1·24, 95% CI 1·01–1·53), but no increased risk with oestrogen alone (HR 0·79, 0·61–1·02), with treatment durations of 5–7 years.

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 These risks are lower than the two-times increased risk for conjugated oestrogen–MPA therapy and 1·33-times increased risk for oestrogen alone estimates reported in the recent Collaborative Group observational analysis

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 for predominantly similar MHT formulations. This discrepancy is consistent with the expectation that observational findings are tempered by high-quality randomised controlled trials. Follow-up of the 27 347 participants in the WHI trials for 18 years provides the most convincing MHT safety data.

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 With mortality follow-up available for more than 98% of participants and 7489 deaths, all-cause mortality did not differ from placebo for daily conjugated oestrogen–MPA therapy (HR 1·02, 95% CI 0·96–1·08) or for conjugated oestrogen only (0·94, 0·88–1·01).

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 Neither oestrogen alone nor oestrogen–MPA were associated with total cancer mortality, or any specific cancer mortality, in the intervention or follow-up phases. For women aged 50–59 years at randomisation, pooled data suggested a significantly reduced all-cause mortality with MHT compared with placebo (HR 0·69, 95%CI 0·51–0·94, p=0·01).

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 This finding emphasises the precariousness of observational data and of evaluating any single effect of MHT in isolation, whether the outcome be a benefit or a risk, as the effects are a composite and clinical decisions are made on the basis of overall effects, including quality of life.

Notably, recommended MHT is now substantially different from that included in the Collaborative Group analysis.

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 Nearly all the data for combined oestrogen—progestogen therapy in the analysis pertained to NETA or MPA. The analysis had insufficient power to draw conclusions about the effects of the preferred progestogens, progesterone (only 50 breast cancer cases included) and dydrogesterone (253 cases). The investigators’ conclusion that progesterone was associated with a two-times increased breast cancer risk if used for 5–14 years was based on only 38 breast cancer cases for this duration of use.

A potentially dangerous consequence of misinterpreting observational data in this context is that early (<45 years) or prematurely (<40 years) menopausal women could stop their MHT. 10% of women have early menopause. Thus, the norm for women younger than 45 years is to be premenopausal. Because early or premature menopause is a hormone deficiency state, breast cancer risk is reduced, but the likelihood of osteoporosis, cardiovascular disease, and premature death is increased.

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 Therefore, for women prematurely menopausal, MHT is physiological therapy that restores overall risks, notably the risk of premature death, back to those of premenopausal woman of the same age.

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The findings from the Collaborative Group analysis deserve to be better contextualised. In isolation, such reports offer a unidimensional perspective on a multidimensional issue, disregarding the profoundly detrimental effects of oestrogen deficiency symptoms for many women, the negative bone and cardiometabolic consequences of menopause, and the diverse beneficial effects of MHT. Even with the best estimates of benefits and risks, the art of medicine resides in listening to each woman’s story and providing care tailored to symptom severity and effect, and each individual’s overall benefit-to-risk profile.

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Menopausal hormone therapy safe for most women at low CVD risk

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Menopausal hormone therapy for bothersome vasomotor or other symptoms is safe and appropriate for most women at low atherosclerotic CVD risk, whereas a nuanced approach is needed for intermediate-risk women, researchers reported.

“Many cardiologists are reluctant to prescribe hormone therapy (HT) to patients with symptoms of menopause because of concerns with CVD risk,” Leslie Cho, MD, director of the Cleveland Clinic’s Women’s Cardiovascular Center, told Healio. “There is confusion around the evidence-based guidelines that support hormone use. We thought this was a perfect time to address this issue, as there has been this enormous resurgence of interest in menopausal hormone treatment and major consumer wellness organizations have entered the fray.”

Graphical depiction of data presented in article

At one time, menopausal HT was almost universally recommended, Cho and colleagues wrote in a review published in Circulation. With the publication of the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI) trial, both of which reported excess CV risk with HT, use of HT declined substantially, Cho said.

However, during the past 20 years, the relationship of CVD risk with timing of menopause, initiation of HT and route of HT delivery has been better understood. Four major North American medical societies — the American College of Obstetricians and Gynecologists, American Association of Clinical Endocrinology, the Endocrine Society, and the North American Menopause Society — now recommend HT in appropriate patients for the management of menopausal symptoms.

“No one recommends hormones for CVD prevention,” Cho said in an interview. “HT does not impact weight or lower heart disease risk. HT is recommended for bothersome menopausal symptoms.”

Ideal candidates for HT

The review, led by the American College of Cardiology Cardiovascular Disease in Women Committee, along with leading gynecologists, women’s health internists and endocrinologists, states that ideal candidates for menopausal HT are women who are younger than 60 years or within 10 years of menopause onset, who have a 10-year estimated ASCVD risk of less than 5% and do not have an increased risk for breast cancer or history of venous thromboembolism.

A more nuanced approach for HT is recommended for women at intermediate CVD risk, defined as women who have diabetes, who smoke, have hypertension, obesity, metabolic syndrome or an autoimmune disease, among other risk factors.

“The presence of CVD risk factors alone does not preclude the use of HT, but a patient’s worsening cardiovascular risk profile around the menopause transition emphasizes the need to optimize primary prevention efforts, including lifestyle and pharmacological management,” the researchers wrote.

“There are many HT formulations, including systemic hormones, transdermal estrogen and progesterone, vaginal estrogen,” Cho said. “The lowest risk is vaginal estrogen because it is not systemically absorbed. Transdermal HT seems to be associated with less of an increase in cholesterol and BP and less risk for development of clots.”

Guidance does not recommend the use of bioidentical hormones, which are not FDA-regulated, Cho said.

‘Be thoughtful’ about menopausal HT

For the WHI, researchers randomly assigned women aged 50 to 79 years without CVD continuous combined oral conjugated equine estrogen (CEE) with medroxyprogesterone acetate or placebo; women without a uterus were randomly assigned to CEE alone or placebo. The initial findings suggested that compared with placebo, risks for CHD, stroke and VTE, including pulmonary embolism, were increased with HT. Subsequent analyses of the WHI, which were age-stratified with longer cumulative follow-up (median duration, 13 years) supported a more nuanced approach to HT, Cho said.

“The WHI initially showed that HT increases risk. That trial included women of all ages, women older than 60 years, those more than 10 years after menopause,” Cho said. “That scared everyone. But what we have learned since then — almost 20 years later — is that starting HT for younger women, and being mindful of HT type and for the shortest duration possible for symptom relief is actually quite safe. The nuanced approach is an important message to convey.”

Cho said for women aged 50 years and older with one or more risk factor for CVD, shared decision-making is key.

“We want to be thoughtful about which hormones are prescribed, and risk for women who have a history of stroke or blood clots, who should never receive HT,” Cho said. “The biggest takeaway is it is important that cardiologists know that HT for low-risk women is very safe. For intermediate-risk women — women with one or more risk factors — think about transdermal formulations. Those at high risk are not candidates for HT. The other important thing is we have to respect patient wishes and what is important for them. Using a nuanced approach and adopting shared decision-making is really important,” Cho told Healio.

For more information:

Leslie Cho, MD, can be reached at chol@ccf.org.

Perspective

Howard Weintraub, MD)

Howard Weintraub, MD

This review is encouraging. There was a time in the 1990s when the beneficial role of estrogens in vascular health seemed clear and convincing. Then, data from HERS and the WHI suggested menopausal HT could be deleterious. Estrogens were vilified in any other form other than transvaginal or for women who began menopause early, age 45 years or younger. Patients experiencing bothersome symptoms would see a clinician only to be told, “Sorry, I don’t have anything to make you feel better.”

We now know that the role of estrogen is more nuanced. Data from WHI show that, if you wait until 10 years or more after menopause, HT can be deleterious, for reasons that are still not completely understood today. It is now clear that there is a benefit to sustaining the estrogen effect; however, there appears to be potential for deleterious activity in some people prescribed menopausal HT, so discrimination between low-, intermediate- and high-risk people is important. The 2018 ACC guidelines for the treatment of CVD notes that menopause is a CVD risk enhancer. Data now suggest estrogen deprivation may explain why.

I do not typically treat vasomotor symptoms, but such symptoms weigh in my decision making. Typically, HT decisions are made in conjunction with an OB/GYN. Menopausal symptoms can be perplexing and disruptive; quality of life suffers for the patient and their family. Professional societies including the North American Menopause Society, Endocrine Society and the American Association of Clinical Endocrinology have all endorsed HT for menopause symptoms when appropriate. What this review offers is a finessing of the way these medications should be delivered, noting clinicians should be selective in who is prescribed HT.

Howard Weintraub, MD

Clinical Director, Center for the Prevention of Cardiovascular Disease
Clinical Professor, Department of Medicine, Leon H. Charney Division of Cardiology
NYU Langone Health

Menopausal hormone therapy doubles risk of breast cancer, Cancer Council NSW says, but experts disagree.

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A women has a mammogram in a doctor's clinic

Concerns hormone replacement therapy could increase breast cancer risk.

Women using hormone replacement therapy to deal with the difficult symptoms of menopause are twice as likely to develop breast cancer than those who have never used it, new research has shown.

The study by Cancer Council NSW was conducted with more 2,000 menopausal women.

But it has been questioned by one women’s health expert, who has said the sample size was too small and biased.

Professor Karen Canfell, director of cancer research at Cancer Council NSW, said a significant proportion of women choose to use menopausal hormone therapy medications, which are effective at relieving specific symptoms such as hot flushes and night sweats.

“The best estimate we have suggests that around 12 per cent of women aged between 40 to 65 are using menopausal hormone therapy, so that’s about 500,000 women,” she said.

Cancer Council NSW looked at data from over 1,200 women with breast cancer and over 800 women who did not have breast cancer.

“What we found was that in women who are currently using menopausal hormone therapy … the risk of developing invasive breast cancer was doubled,” Professor Canfell said.

She said it was the first time this had been examined on a large-scale in Australia, and that the finding was significant.

“The good news is that in our study, as in international studies, what we found was that the risks are not elevated in women after they stop using menopausal hormone therapy,” Professor Canfell said.

The study indicated that the risk would return to baseline within five years of stopping the hormonal therapies, while international evidence suggested it could take two years or less.

Study refuted as ‘crude’ and ‘simplistic’

Professor Susan Davis, the director of the Women’s Health Research Program at Monash University, said she had concerns about the way the study was conducted.

“It really is a fairly simplistic and, I’d say, crude analysis because of the way the information was collected,” Professor Davis said.

“In this study the observations were from women who had had breast cancer who decided that they wanted to complete a questionnaire.

“And we know that women who choose to participate in this study are different to those who choose not to, and that introduces a bias.”

Professor Davis said Cancer Council NSW’s results varied dramatically from much larger studies.

She said poor-quality research could misinform community and misinform clinical practice.

“So the gold standard of research is a randomised control trial and we have that from the Women’s Health Initiative, that involved 27,000 women,” Professor Davis said.

“The study that we’re discussing now involved 1,200 women who developed breast cancer and 800 control, so it’s very small.”

But Cancer Council NSW’s Professor Canfell defended the study.

“This is the same evidence that’s informed the positions of regulatory agencies worldwide: the FDA, the Medical Healthcare Regulatory Agency in the UK and Australia’s TGA,” she said.

“So we’re not saying anything that’s different from the international evidence.

“It’s just a timely reminder and further evidence, if it were needed, that menopausal hormone therapy has risks as well as benefits.”