‘Need to change perceptions on menopausal hormone therapy’

FDA removes black box warning…impact of changing interpretation of WHI study

“Treatment within 10 years of menopause is important”…rise of personalized approaches

With the US Food and Drug Administration (FDA) recently removing the Black Box Warning imposed on menopausal hormone therapy (MHT) products, the likelihood of a shift in perception is growing within Korea’s obstetrics and gynecology clinical field.

While there has long been a strong tendency to avoid treatment due to concerns about the risk of breast cancer and cardiovascular disease, there is now a growing emphasis on the need for personalized treatment that takes into account the patient’s age, time of menopause, and risk factors.

In particular, experts pointed out that the findings of the US Women’s Health Initiative (WHI) study had been excessively generalized to women in early menopause, and stressed that the long-term health benefits of early treatment, such as the prevention of cardiovascular disease, osteoporosis, and dementia, should also be considered.

In a recent meeting with DailyPharm, Eun Sil Lee, Professor of Obstetrics and Gynecology at Soonchunhyang University Seoul Hospital, and Tae-Hee Kim, Professor of Obstetrics and Gynecology at Soonchunhyang University Hospital Bucheon, assessed that this FDA action could serve as an opportunity to fundamentally redefine existing perceptions of MHT, going beyond the mere removal of warning labels.

(From the left) Professor Eun Sil Lee (Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital) and Professor Tae-Hee Kim (Obstetrics and Gynecology, Soonchunhyang University Hospital Bucheon)

The two professors particularly pointed out that although the 2002 WHI study was conducted on a patient population different from actual women in early menopause, the findings were subsequently applied uniformly to women of all ages, creating excessive fear toward hormone therapy.

Based on the study results, the FDA introduced Black Box Warnings for MHT products in 2003. Following this, concerns over breast cancer, cardiovascular disease, and dementia risks spread rapidly, causing hormone therapy prescriptions to decline sharply worldwide. However, as more age-specific and menopause timing-based reanalyses accumulated in recent years, the FDA initiated procedures last November to remove the warning.

Experts point out that the WHI study results were overgeneralized.

The WHI study included women with an average age of 63, many of whom already had a significant number of risk factors for cardiovascular disease. Another limitation cited is that the study used a combination of hormones that is no longer widely used today. Subsequent age-specific analyses showed that for women who began treatment within 10 years of menopause, particularly those in their 50s, there was no clear increase in the risk of cardiovascular disease or dementia, and some studies even suggested possible preventive effects.

In practice, MHT has long been used as a representative menopause management therapy, having been proven effective not only in alleviating menopausal symptoms such as hot flashes, sleep disturbances, and depression but also in preventing osteoporosis. However, following the publication of the WHI study, concerns about breast cancer risk spread rapidly, leading to a strong trend in Korea toward discontinuing or avoiding the treatment.

Recently, there has been growing discussion that MHT should be reevaluated from a “well-aging” perspective, one that goes beyond simple symptom management to include cardiovascular health, osteoporosis prevention, and the management of healthy life expectancy. As life expectancy increases and women spend longer periods living after menopause, experts argue that both risks and benefits of treatment should be evaluated in balance.

The two professors emphasized, “MHT should not be oversimplified solely in terms of breast cancer risk. It should instead be approached from the perspective of personalized treatment that comprehensively considers patient age, menopausal timing, and overall health status. When treatment begins at the appropriate time, positive effects can be expected not only for quality of life improvement but also for long-term health management.”

Q. How do you evaluate the FDA’s recent removal of the MHT Black Box Warning?

Professor Tae-Hee Kim (Obstetrics and Gynecology, Soonchunhyang University Hospital Bucheon)

Professor Tae-Hee Kim: I view this FDA action as an important opportunity to reevaluate the previously excessive perception of MHT risks based on evidence.

The patients included in the WHI study had a median age of 63 and included women with cardiovascular risk factors. They differed from actual women in early menopause who typically begin hormone therapy. Moreover, the study used hormone combinations that are rarely used today, making it difficult to generalize the results to all patients.

I think this decision carries significance in reorganizing overly emphasized risks so that women in early menopause who may benefit from hormone therapy do not avoid treatment excessively.”

Professor Eun Sil Lee: The previous black box warning stated that prescribing MHT increased the risk of breast cancer, cardiovascular disease, and dementia, which significantly heightened patients’ fears. In fact, the frequency of hormone therapy use decreased significantly following the WHI study.

However, subsequent age-specific analyses yielded different results. For women in their 50s who began treatment within 10 years of menopause, there was no clear increase in risk. On the contrary, the possibility of preventing cardiovascular disease or dementia was raised. Ultimately, this means that the timing of when hormone therapy is started is what matters.

Q. How should the safety of MHT be evaluated?

Professor Tae-Hee Kim: Previously, there was a strong perception that taking hormones increased the risk of cardiovascular disease and dementia, but in fact, these findings should be viewed as results from women who started treatment in their 60s and 70s.

On the other hand, data is accumulating showing that starting treatment in one’s 50s, during the early stages of menopause, may actually have preventive effects against cardiovascular disease and dementia. Ultimately, the key issue is not simply whether or not to take hormones.

Factors such as age, menopausal timing, and cardiovascular risk factors must all be considered comprehensively. I believe safety is determined by individualized treatment strategies tailored to each patient.

Professor Eun Sil Lee: I believe the most important factors when evaluating safety are the patient’s age and the timing of menopause.

In reality, women in the early stages of menopause often do not have a relatively high risk of cardiovascular disease. Rather, during this period, as hormone levels drop sharply, vascular health deteriorates, and changes such as decreased bone density, sleep disorders, and feelings of depression begin to manifest in earnest.

Conversely, if a patient has already progressed into her 60s with advanced atherosclerosis, the approach may differ. In advanced atherosclerosis, hormone therapy could potentially affect thrombosis risk. In the end, the key issue is who starts treatment and when.

In actual clinical practice, many patients with severe menopausal symptoms hesitated to pursue treatment due to fears such as ‘Won’t this increase my dementia risk?’ or ‘Won’t this cause cardiovascular disease?’ But recently, the concept of individualized treatment considering age, risk level, and menopausal timing has become increasingly important.

Ultimately, I believe the safety of MHT is not an issue that can be explained in a one-size-fits-all manner; it must be assessed by comprehensively considering the patient’s health status and the timing of treatment.

Q. How are differences in safety between products distinguished in actual clinical practice?

Professor Eun Sil Lee: The approach to hormone therapy fundamentally differs depending on whether the patient has a uterus. Women without a uterus can use estrogen-only therapy, but women with a uterus must use progesterone in combination to prevent endometrial cancer.

The characteristics of treatment differ depending on which progesterone is used. Appropriate therapy inevitably varies according to patient age, symptoms, risk level, and preference.

Professor Tae-Hee Kim: Rather than saying a specific product is absolutely better, it is more accurate to view each hormone therapy as having distinct characteristics.

It is important to select the most suitable medication by considering the patient’s lifestyle, symptoms, and health status. Ultimately, individualized treatment through consultation with a specialist is key.

Q. How do you evaluate the breast cancer risk associated with MHT prescriptions?

Professor Eun Sil Lee (Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital)

Professor Eun Sil Lee: In reality, differences exist depending on the medication. European studies showed that combinations of estrogen and natural progesterone did not demonstrate a clear increase in breast cancer, while some synthetic progesterone combinations showed tendencies toward increased risk.

However, even if long-term use carries some increased risk, the absolute risk itself is interpreted as not very large. Above all, regular screenings are crucial.

Women receiving hormone therapy tend to undergo regular screenings more consistently, and management is possible through early detection. Ultimately, I think accurate explanations are needed so patients do not abandon treatment based solely on vague fear.

Professor Tae-Hee Kim: Many women have a vague fear that taking hormone therapy will cause breast cancer. But actual data show that the issue is not that simple.

Even in the WHI study, women without a uterus did not show an increase, but rather a tendency toward reduced breast cancer incidence. European studies also found differences in breast cancer risk according to progesterone type. Some medications showed no significant increase.

Of course, it cannot be said that taking hormones absolutely prevents breast cancer. However, the important point is that breast cancer mortality did not increase. In fact, overall mortality was lower.

Benefits such as improved quality of life, fracture prevention, and cardiovascular disease prevention must also be considered together. Individualized treatment based on family history and risk level is important.

Q. How do you predict MHT prescriptions will change in the Korean market going forward?

Professor Tae-Hee Kim: I believe changes in perception toward MHT will clearly emerge in Korea as well. In particular, as life expectancy increases, interest is continuing to grow not only in living longer, but in aging healthily—that is, in ‘well-aging’ and ‘anti-aging.’

Women now live for more than 30 to 40 years after menopause. Ultimately, how healthily this period is managed has become extremely important. From that perspective, hormone therapy should be viewed not merely as symptom control for hot flashes or sleep disorders, but as part of a healthy lifespan management strategy.

Most important is the timing of treatment initiation. Starting treatment within 10 years after menopause or before age 60 is absolutely advantageous. Diseases such as cardiovascular disease, dementia, and osteoporosis become difficult to reverse once they progress. Therefore, we must approach them from a preventive perspective, which requires starting management from the early stages of menopause.

In actual clinical practice, many patients experience major declines in quality of life due to osteoporotic fractures, fall risk, sleep problems, and joint pain. Hormone therapy can help improve these issues as well.

Professor Eun Sil Lee: I believe the current prescribing environment is likely to expand further. However, rather than simply increasing prescriptions across the board, “personalized treatment” tailored to each patient’s characteristics will become more important.

After menopause, vascular health deteriorates rapidly due to a decrease in estrogen. Atherosclerosis begins to progress, and bone density also decreases rapidly. Therefore, in women in the early stages of menopause, hormone therapy can play a positive role in preventing osteoporosis and maintaining vascular health.

Conversely, the approach may differ for older women in whom atherosclerosis has already progressed significantly. Ultimately, this means that the patient’s age, vascular condition, and the timing of menopause must all be taken into account.

Recently, the FDA has also emphasized the need for an approach that takes age and the timing of menopause into account. In fact, the FDA has recommended starting treatment within 10 years of menopause or before the age of 60.

Most importantly, patient perception itself must change. Until now, the perception that ‘hormone therapy is always dangerous’ has been too strong. But now patients are beginning to think about both quality of life and healthy lifespan.

Going forward, rather than simply enduring menopausal symptoms, interest in how to maintain health after menopause is likely to increase further. In that process, it will become important for patients to consult sufficiently with medical professionals and choose treatments suited to themselves.