Endocrine Today 20th Anniversary

Endocrine Today 20th Anniversary

Issue: May 2022

Healio interviews

Disclosures: Minkin reports serving as a consultant for Pfizer and TherapeuticsMD. Santoro reports serving as a consultant for Ansh Labs and Ember, and serving on scientific advisory boards for Menogenix, Astellas and QUE Oncology. Manson and Thacker report no relevant financial disclosures.
April 08, 2022
7 min read

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

Issue: May 2022

Healio interviews

Disclosures: Minkin reports serving as a consultant for Pfizer and TherapeuticsMD. Santoro reports serving as a consultant for Ansh Labs and Ember, and serving on scientific advisory boards for Menogenix, Astellas and QUE Oncology. Manson and Thacker report no relevant financial disclosures.
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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.

Nanette Santoro

“The findings made headlines for the barely over statistically significant increase in heart disease and the barely under statistically significant increase in breast cancer,” Nanette Santoro, MD, professor and the E. Stewart Taylor Chair of Obstetrics & Gynecology at the University of Colorado School of Medicine, told Healio. “All the public saw was that HT caused heart disease and gave you breast cancer. About 75% of HT prescriptions and medications were thrown away.”

Since then, researchers have further refined knowledge on the benefits and risks of menopausal HT. While HT may not protect against CV events as many thought in the 1980s and 1990s, it provides menopausal symptom relief and has a favorable benefit-risk profile for symptomatic women in early menopause, JoAnn E. Manson, MD, DrPH, MACP, chief of the division of preventive medicine at Brigham and Women’s Hospital, and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Healio.

JoAnn E. Manson

“The pendulum really swung too far to the other side,” Manson said. “Prior to the WHI, there was excessive use of HT for prevention of chronic disease, for women in late menopause and for women who didn’t have moderate to severe symptoms of menopause. Shortly after the WHI findings, the sea change in practice was the major underutilization of HT for any purpose, even for the management of distressing menopausal symptoms in early menopause. Fortunately, over the subsequent decade, additional detailed analyses showed there were many nuances to the WHI findings and younger women did quite well on HT.”

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. Mary Jane Minkin, MD, FACOG, clinical professor in the department of obstetrics, gynecology and reproductive sciences at Yale Medical School, said the increased risk for breast cancer was extremely slight to begin with and was found only for women receiving estrogen plus progestin. More WHI data published in 2004 showed women receiving estrogen alone had no increased breast cancer risk.

Mary Jane Minkin

“We now know the kind of progesterone that is used with the estrogen to protect the lining of the uterus makes a difference,” Minkin told Healio. “There’s a fair amount of data from Europe that shows that micronized natural progesterone does not increase the risk of breast cancer with the estrogen compared with synthetics.”

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.

“Women who initiate HT earlier in menopause tend to do better than women who are starting much later after a longer period without exposure to their endogenous estrogen,” Manson said. “Overall, the evidence has supported the timing hypothesis.”

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.

“There is an appreciation that HT is the best treatment we’ve got for symptom relief, and some women feel so awful off of it and cannot take alternatives that there is a greater tolerance for longer-term therapy, while appreciating there are some risks of long-term therapy,” Santoro said. “Guidelines have started to harmonize across multiple societies and that is a good thing.”

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.

“There continues to be some confusion and anxiety about use of HT,” Manson said. “But it has decreased substantially since the early 2000s, the years shortly after the publication of the main WHI findings for estrogen plus progestin.”

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.

“These drugs I hope are going to be really helpful for women with breast cancer who I can’t give estrogen to,” Minkin said. “These drugs are not a substitute for estrogen. They’re great and are going to help with hot flashes tremendously, much better than anything else we have other than estrogen right now. But it’s still not going to take care of their skin, it’s still not going to take care of their vagina, it’s not going to prevent osteoporosis. It’s a great drug, but it doesn’t do all the stuff that estrogen does. I don’t think it’s going to be a replacement, but it’s going to be another option that we have.”


Anderson GL, et al. JAMA. 2004;doi:10.1001/jama.291.14.1701.

Compounded Bioidentical Hormone Therapy. www.endocrine.org/advocacy/position-statements/compounded-bioidentical-hormone-therapy. Published Oct. 2, 2019. Accessed March 31, 2022.

Kolata G. Study is halted over risk seen in cancer risk. The New York Times. www.nytimes.com/2002/07/09/us/study-is-halted-over-rise-seen-in-cancer-risk.html. Published July 9, 2002. Accessed March 31, 2022.

Manson JE, et al. N Engl J Med. 2003;doi:10.1056/NEJMoa030808.

Manson JE, et al. JAMA. 2013;doi:10.1001/jama.2013.278040.

Minkin MJ. Obstet Gynecol Clin N Am. 2019;doi:10.1016/j.ogc.2019.04.008

NAMS Advisory Panel. Menopause. 2017;doi:10.1097/GME.0000000000000921.

Rossouw JE, et al. JAMA. 2002;doi:10.1001/jama.288.3.321.

For more information:

JoAnn E. Manson, MD, DrPH, MACP, can be reached at jmanson@rics.bwh.harvard.edu.

Mary Jane Minkin, MD, FACOG, can be reached at maryjane.minkin@yale.edu.

Nanette Santoro, MD, can be reached at nanette.santoro@cuanschutz.edu.

Holly L. Thacker, MD, FACP, CCD, NCMP, can be reached at thackeh@ccf.org or www.speakingofwomenshealth.com.