20 years of data lead to changes in perceptions, usage of menopausal HT

Posted on April 08, 2022

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Source: Healio

During the past 2 decades, Endocrine Today has reported on the latest developments in hormone therapy for symptoms associated with menopause. For its 20th year, the publication is taking a look back.

Twenty years ago, findings from a pivotal study dramatically changed the public’s perception — as well as that of some health care providers — surrounding menopausal HT.

Takeways from the past 20 years of menopausal HT
According to the timing hypothesis, HT is safer for younger women who initiate it closer to the start of menopause and most medical societies endorse the use of HT for the treatment of vasomotor symptoms.

In the 1980s, several studies found women who took estrogen therapy had a reduced risk for coronary heart disease, leading many to believe that menopausal HT could be protective against adverse cardiovascular outcomes. All of that changed in July 2002.

On July 17, 2002, JAMA published a study on the risks and benefits of estrogen plus progestin from the Women’s Health Initiative randomized controlled trial. In the study, estrogen and progestin therapy was associated with slightly increased risks for total CVD (HR = 1.22; 95% CI, 1.09-1.36), stroke (HR = 1.41; 95% CI, 1.07-1.85) and pulmonary embolism (HR = 2.13; 95% CI, 1.39-3.25). In addition, participants using estrogen and progestin also had a borderline statistically significantly increased risk for breast cancer (HR = 1.26; 95% CI, 1-1.59). The trial was stopped 3 years early on May 31, 2002, due to “health risks that exceeded health benefits over an average follow-up of 5.2 years.”

What many experts remember from 20 years ago is not the publication of the article in JAMA. Instead, it was the media frenzy that caused panic among women using menopausal HT on July 9, 2002, when several media outlets broke the news on the findings prior to the study’s publication.

More clarity after WHI

In the years after the initial WHI findings, more data have come out on the associations between menopausal HT and the increased risk for breast cancer and CHD in the WHI. More WHI data published in 2004 showed women receiving estrogen alone had no increased breast cancer risk.

Data published since original WHI findings also shed more light on the link between menopausal HT and CHD. The 2004 data on the WHI’s estrogen-only arm revealed a reduced risk for CVD in women who began estrogen before the age of 60 years. In age-stratified analyses led by Manson and published in JAMA in 2013, women aged 50 to 59 years taking estrogen alone had a lower risk for CHD compared with those taking placebo, but the opposite was true in older women. In analyses driven largely by older women, those taking estrogen and progestin had a significantly increased risk for CHD at 1 year (HR = 1.8; 95% CI, 1.08-2.99), but the risk declined in the years that followed.

Holly L. Thacker

“When they put out the adjudicated data, the increase in CVD was only in the aged 70 and older women,” Holly L. Thacker, MD, FACP, CCD, NCMP, director of the Center for Specialized Women’s Health at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, told Healio. “Several years later, when they released the age-stratified data, women who were younger than 60 years who took hormones for a decade had less CVD. It took us almost a decade to unravel this.”

The new data provided researchers with evidence of the so-called timing hypothesis, where younger women who are closer to the onset of menopause have more favorable outcomes with menopausal HT compared with older women. The timing hypothesis was a key part of a position statement on menopausal HT released by the North American Menopause Society (NAMS) in 2017. In that statement, the organization noted that women aged at least 60 years starting HT or more than 10 to 20 years removed from menopause onset may have increased risks for CHD, stroke, thromboembolism and dementia, while younger women starting HT closer to the onset of menopause tend to have more favorable effects of treatment than older women.

Today, most medical societies have reached consensus regarding menopausal HT. Most guidelines align with the position statement of NAMS, which stated that HT remains the best treatment for vasomotor symptoms and genitourinary syndrome of menopause.

Building back trust

New data have provided more clarity on the findings of the WHI, but the impact of the original WHI data published in 2002 and the reaction from patients had ripple effects that continue today.

Some fears surrounding HT have subsided as a new generation of younger women who do not have a memory of the WHI findings being big news in 2002 are now beginning to use menopausal HT.

“The women that are starting to use HT now, the Generation X women, are different than the baby boomers,” Thacker said. “They weren’t constantly exposed to negative headlines and we’re not really seeing negative headlines about HT like we constantly were 20 years ago. I think the media plays a huge influence. Women use the internet for health information, and now this generation of women that is entering menopause, they’re savvy. They know how to seek out different sources of information and it’s a lot easier than 20 years ago.”

Another effect the 2002 WHI news had on the HT market was to open the door for compounded bioidentical hormones, products that are marketed to women as safer and more effective alternatives to menopausal HT. In recent years, medical societies, including the National Academy of Medicine, Science and Engineering, NAMS and the Endocrine Society, have moved to discourage women from taking the formulations, which are not approved by the FDA and can have dose inconsistencies and impurities.

Instead of compounded hormones, researchers look toward nonhormonal options that could provide an alternative to HT. In 2014, the FDA approved 7.5 mg paroxetine (Brisdelle, Noven Pharmaceuticals), a selective serotonin reuptake inhibitor, for the treatment of moderate to severe vasomotor symptoms.

A new nonhormonal option currently in clinical trials is fezolinetant (Astellas Pharma), a selective neurokinin-3 receptor antagonist that blocks neurokinin B binding on the kisspeptin/neurokinin/dynorphin neuron in the hypothalamus to reduce the amount and severity of vasomotor symptoms. As Healio previously reported, women taking 30 mg or 45 mg of once-daily fezolinetant had reductions in the number and severity of hot flashes at 4 weeks and 12 weeks compared with placebo. Minkin said the agent, once approved, could give providers another effective alternative for women who cannot take HT.