Women’s hormonal health research and care: the times, they are a-changin’

Introduction

The anthem “The Times They Are A-Changin’” is a 1964 song by singer-songwriter Bob Dylan that is still appropriate today. The American Society of Clinical Oncology (ASCO) was created that year, and its purpose has remained steadfast—“improve the care of people with cancer” (1). ASCO’s current strategic plan includes six shared values: “... be exceptional and trustworthy, share knowledge and expertise, contribute to society, foster robust interchange, perpetuate valuable learning, and elevate every experience”. In this invited editorial, we aim to bridge the gap between cancer care and prevention and the complex world of women’s hormonal health. This is relevant in the context of a recent publication that analyzed the impact of hormone therapy (HT) in the Women’s Health Initiative (WHI) on the risk of ovarian cancer (2). The field of women’s hormonal health across the lifespan should emulate the shared values of ASCO. It is time to advance from the National Institutes of Health (NIH) WHI 1.0 of the 1990s to an entirely new phase, a global WHI 2.0 (3).

Historical perspective of cancer care and women’s health

In 1964, the patient was the focus of care. Most practices were independent, small, organized around relationships, patient loyalty, professional duty, personal and family care, with an emphasis on continuity and access. Unfortunately, it was often also paternalistic and lacked transparency about the quality of care. Furthermore, the system could be fragmented; information sharing with parts of the larger health care system for specialty care was limited.

By this time, the National Cancer Institute (NCI) was already leading important research with international collaboration (4). By 1961, the NCI had funded 86 international research grants in 23 countries. This international collaboration was responsible for groundbreaking advances in promoting standardized pathology reporting and diagnosis, as well as in statistical and epidemiological research, and in establishing evidence that environmental factors are significant contributors to the development of certain types of cancers (4).

Meanwhile, women’s health research lagged far behind and received no dedicated funding from the NIH. In 1977, the FDA recommended excluding women of childbearing potential from phase I and phase II trials (5). Women’s health needs were a low priority in science and medicine. There was no enforced NIH policy encouraging women’s health research until the establishment of the Office of Research on Women’s Health in 1990 (5). It is unsurprising, given the relative lack of historic funding for foundational research in women’s health, that many diseases that affect only women have limited effective treatment options. As a result, there is widespread dissatisfaction among women regarding care for common conditions.

WHI: context, criticisms, and the modern perspective

In the early 1990s, the WHI was developed in response to outcry about the lack of women’s health research (5). The HT component was a randomized, double-blind, placebo-controlled trial including 27,500 women, designed to determine whether the HT formulations commonly prescribed at the time were effective for primary prevention of coronary artery disease. Hip and other fractures were included as secondary outcomes, and breast cancer as a potential adverse outcome (6,7). Women with no uterus were randomized to receive oral conjugated equine estrogen (CEE) 0.625 mg/day or placebo, and women with a uterus were randomized to placebo or CEE 0.625 mg/day plus continuous 2.5 mg/day of medroxyprogesterone (MPA) to protect against endometrial hyperplasia (8). In 2002, the CEE plus MPA arm of the WHI was ended early due to an increase in the number of invasive breast cancers above the predefined threshold in the treatment arm (6). Other adverse outcomes in the CEE + MPA arm included increased cardiovascular events, increased strokes, and increased venous thromboembolic disease. The treatment group experienced fewer cases of colorectal cancer and hip fractures. All-cause mortality did not differ between the treatment and placebo arms (6).

The announcement of the early end of the WHI was associated with widespread negative news headlines, such as the BBC headline “HRT Linked to Breast Cancer” (9). The tone of subsequent news coverage caused distress among millions of women on HT, and the rate of HT initiation and continuation fell significantly (10). Over time, news coverage shifted to features about the confusion of individual women who were forced to discontinue HT without adequate explanation and without a viable replacement for the symptoms of estradiol deficiency (9). Clinicians frequently underestimate the negative impact vasomotor and genitourinary symptoms have on quality of life and impact work performance for a majority of women (11). Two years after the NIH ended the MPA arm of the study, they also ended the CEE-only arm due to a lack of overall benefit; conflicting findings and nuance were underrepresented in media coverage (7,12). Unfortunately, the findings of the 2002 WHI study were generalized to younger, symptomatic women and women who had had a prior hysterectomy for whom estrogen-only HT would have been appropriate (12).

In the years since the NIH WHI, many criticisms have been levied against its design. A major criticism is that women with vasomotor symptoms were excluded from this double-blinded study. Women experience the most symptoms around the menopause transition; symptoms tend to wane as they reach the late menopausal life stage. The exclusion of these women meant that the women who were most likely to benefit from HT in clinical practice were not able to participate in the study. A second criticism is the type of HT that the study provided to women. A 1986 NEJM report, published well before the design of the WHI, indicated that the transdermal administration of 17-beta estradiol avoided several adverse effects linked with oral estrogens (13). These adverse effects, due to the first-pass hepatic metabolism, include increased risk of gallbladder disease and venous thromboembolism (8). A general principle of clinical research consent is to inform participants about potentially safer and more effective treatment methods. The NIH WHI consent form failed to discuss the potentially safer transdermal alternative (14).

Decades have passed since the publication of the NIH WHI, and the understanding of how to safely prescribe HT in menopause has subsequently improved. Subgroup analysis of the WHI results based on age showed that the risk of cardiovascular events more closely matched placebo for younger women, aged 50–59 years (10). The American College of Cardiology now recommends that systemic HT is appropriate for younger, healthy menopausal women experiencing bothersome vasomotor symptoms (15). Current data suggest that transdermal estradiol rather than CEE does not increase the risk of VTE (10). Furthermore, data from a systematic review and meta-analysis indicate that use of oral micronized progesterone rather than MPA for up to 5 years as part of menopausal HT does not increase breast cancer risk (16). Menopausal HT significantly reduced the risk of any clinical fracture, major osteoporotic fracture, and hip fracture (10). Hip fractures are associated with significant morbidity and mortality. The Menopause Society recommends that HT is the most effective treatment for vasomotor symptoms and the genitourinary syndrome of menopause. Treatment should be individualized with periodic reevaluation of the benefits and risks of continuing therapy (8).

The legacy of the NIH WHI study and the ongoing confusion surrounding women’s decision-making about HT persist. Many women feel uncertain about how to find personalized and reliable advice, and most physicians do not receive adequate training to guide women (17). Despite evidence that HT reduces all-cause mortality, many women tend to overestimate the risks (12).

Analysis of the current study

Chlebowski et al. present results from long-term follow-up data from the NIH WHI menopausal HT randomized trials (2). The CEE plus MPA trial was stopped after 5.6 years, and the CEE alone trial was stopped after 7.2 years. Their analysis of 20-year follow-up data concludes that the administration of CEE alone increased the incidence and mortality of ovarian cancer. In contrast, administering CEE with MPA did not have this effect. Additionally, CEE with MPA reduced the risk of endometrial cancer (2). The finding of increased risk of ovarian cancer in estrogen-only HT users is consistent with that seen in prospective observational studies. However, prospective observational studies differ from the current finding in that they also suggested increased ovarian cancer in women taking an estrogen plus progestogen (18).

Perhaps most importantly, during 18-year follow-up of the WHI HT trials, there was no difference in all-cause mortality or total cancer mortality between both HT arms and placebo (10). It is time for the sun to set on further analysis of the NIH WHI of 1992. More physiologic replacement of 17-beta estradiol is now feasible, avoiding the first-pass liver effect of oral estrogens, such as CEE used in the WHI. Some of the cancer risks related to HT remain unclear, but the thromboembolic risk seen in the WHI can certainly be minimized with parenteral estradiol administration. Women who benefit from HT today are on average much younger than the study population and may have different cancer risks. Menopausal HT has risks, but it also has benefits, and women deserve clinicians who are educated in the topic and can offer individualized treatment options for each woman based on her symptoms, personal risks, and preferences.

A shifting paradigm

Times are changing, and women’s health is finally receiving the focused attention it deserves. A recent editorial in Nature proclaimed that menopause research is globally underfunded and that “something experienced by half of humanity is not more studied is little short of scandalous” (19). Following hearings on menopause, the Australian Parliament released a report in September 2024 that is expected to foster significant changes (6). Notably, the committee report recommended that the Department of Health and Aged Care “... commission research to establish a comprehensive evidence base about the impact of menopause and perimenopause on women in Australia”. An independent database providing unbiased subject matter expertise in this area will advance women’s health worldwide. The United States’ NIH finally established a category for menopause research in 2023 and is preparing a research agenda (19). The NIH has allocated $58 million for menopause research and is requesting $154 million for the Office of Women’s Health Research in 2025. For comparison, $7.22 billion was allocated to the NCI for 2025 (20).

There is also currently a worldwide cultural shift recognizing the importance of increased emphasis on women’s health. Although it was a taboo topic just a few years ago, celebrities are now discussing their experience with menopause and helping to build menopause related companies. Between 2022 and 2024, there was a fivefold increase in the number of clinicians applying to take the Menopause Society certification exam (19). In the last few years, there has been development of at least 50 new companies in the biopharmaceutical, consumer goods, digital technology, medical devices, and medical care sectors. Philanthropists are contributing funds and founding institutes dedicated to improving women’s reproductive longevity and lifespan. Research and societal conditions that have caused the disparities in women’s health that are present now will hopefully be in the past.

Aspirational agenda

Establishing a global anchor for women’s comprehensive health research and care is vital. With its history of international collaboration, the NCI Cancer Centers Program exemplifies an excellent model for a worldwide WHI 2.0. A similar model could connect women’s comprehensive healthcare with research worldwide. Modern technological building blocks could improve patient access, enhance the quality of clinical care, support clinical research, manage public health, and lead to better health outcomes similar to the revolution in cancer care that occurred in the second half of the 20^th and early 21^st centuries. While a focus on disease is understandable, a more integrated approach with greater emphasis on individuals’ needs would be a welcome transition.

Modern tools in human subject research allow for data collection through online surveys. These can effectively gather granular data about women’s experiences, attitudes, beliefs, and quality of life. Such data would inform the creation of a comprehensive evidence-based database for women’s health. While efficient, there is a concern that online surveys may compromise data integrity, quality, and validity. These risks include fraudulent or inattentive responses from human participants and even automated systems designed to disrupt the survey data (21). One report supports the viability of developing a global digital medical hub for women’s hormonal health, focusing on primary ovarian insufficiency (22). A digital medical hub combines global digital connectivity, the community-building power of social media, and peer-reviewed research.

Times are also changing dramatically regarding the future of artificial intelligence (AI)-enabled health. AI in health research has the potential to be transformative if applied thoughtfully and with appropriate oversight. Thus far, AI has shown promise in clinical scenarios requiring evaluation of images, including embryo evaluation in in vitro fertilization (IVF), with a significant increase in live birth rates for mothers over the age of 35 years (23). AI models are helpful in identifying patients at high risk of adverse outcomes, such as preterm pre-eclampsia, large for gestational age babies in women with gestational diabetes, and intra/post-partum hemorrhage (23). It is improving pharmaceutical development by identifying new therapeutic targets, predicting protein structures, and enhancing chemical designs, which is promising for reducing time and cost for drug development (24). Despite this promise of AI in the research setting, caution must be exercised. AI can exhibit biases, risks compromising data privacy, may misinterpret prompts, and can produce factually incorrect outputs (25). Strict attention must be paid to regulating this technology to ensure that it is accurate, ethical, and benefits society.

Conclusions

The primary challenge in maintaining the ideal conditions for women’s hormonal health research and care will be keeping the needs of individual women at the forefront. What do women prioritize concerning their health? How can a system engage women as they navigate the women’s health ecosystem that holds significant potential benefits yet presents uncertain risks? Essential components for creating a robust technical ecosystem for women’s health research and care will require honoring their cultural and familial heritage, fostering optimism, sharing benefits, and demonstrating trust and commitment. The technical ecosystem must cultivate a personal care atmosphere characterized by respect. ASCO’s six shared values also resonate: “... be exceptional and trustworthy, share knowledge and expertise, contribute to society, foster robust interchange, perpetuate valuable learning, and elevate every experience” (1). A global WHI 2.0 would foster international collaboration and use technology to promote medical advancements. This would provide a comprehensive solution for health services and research, virtual consultations, and data management. The enterprise would connect with recruitment efforts for active clinical research studies. It would provide patients, clinicians, and health researchers with convenience, flexibility, and efficiency.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-331/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-331/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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