Reinterpreting WHI and Rethinking GSM: Insights from Caroline Mitchell, MD, MPH

At The Menopause Society 2025 Annual Meeting, Patient Care spoke with Caroline Mitchell, MD, MPH, associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, about the direction of research into the genitourinary syndrome of menopause and also about the encouraging progress in understanding of hormone replacement therapy. She voiced concerns about the former topic and clarified the facts on the latter in the short video above.

GSM affects more than half of menopausal women, with approximately 65% experiencing symptoms within the first year and up to 85% after 6 years.¹ However, the treatment landscape for GSM most definitely faces challenges, Mitchell said. "I think people are less focused on [GSM] etiology. The assumption is that it is all about the estrogen, it's about hormones, or it's about tissue changes, and if we target those things with a type of therapy, we'll just make things better." While topical estrogen does remain the gold standard treatment, emerging interventions such as fractional CO₂ laser therapy have shown promise in uncontrolled studies.^2,3 However,"the sham-controlled studies show that it's essentially a placebo effect, and I think there is a very large placebo effect," Mitchell pointed out. She added, "honestly, if you feel better, who cares? Although you probably care if you paid $3,000 to feel better when $50 would have been fine." Closing the topic she said, "My hope would be that we would be doing some of the more basic science work about the pathophysiology of GSM, and I don't see a lot of that."

For more than 2 decades, the clinical landscape surrounding hormone replacement therapy (HRT) for menopausal symptoms has been shaped by the initial findings of the Women's Health Initiative (WHI) study, published in 2002. The early WHI results led to widespread fear about HRT use and a dramatic decline in prescriptions,⁴ as black box warnings were applied to these medications citing increased risks of breast cancer, cardiovascular disease, and dementia.

To clear up any misunderstanding that the original findings have been "refuted," Mitchell emphasized that recent comprehensive reviews have led to a more nuanced interpretation of the WHI data, recognizing that the highest risks were observed in women in their late 60s and early 70s who initiated therapy long after menopause onset.⁴ "Those are the people with the highest risk, and that was interpreted very broadly when the first study came out, so now I think there is nuance," she said. This reanalysis has culminated in a significant policy shift: in November 2025, the FDA announced the removal of black box warnings from HRT products for menopause, following a comprehensive review of scientific literature and expert panel consultation.⁵ The updated guidance now recommends initiating HRT within 10 years of menopause onset or before age 60 for women without contraindications.⁵

The following transcript was lightly edited for style.

Patient Care: How do you see the field evolving in the next five to 10 years in terms of looking at etiology and treatment? Where are we going?

Mitchell: I wish I had a positive answer. I think people are less focused on etiology. The assumption is that it is all about the estrogen, it's about hormones, or it's about tissue changes, and if we target those things with a type of therapy, we'll just make things better.

However, things like the fractional carbon dioxide laser, which is supposed to increase blood flow, should theoretically reverse the changes we associate with the decrease in circulating estrogen. The sham-controlled studies show that it's essentially a placebo effect, and I think there is a very large placebo effect in studies in this area, which honestly, if you feel better, who cares? Although you probably care if you paid $3,000 to feel better when $50 would have been fine. That is what I worry about in this space—that there are interventions out there doing cohort studies, single-arm studies, where there's no placebo control. Sure, people feel better, but do they need to buy a fancy device? Do they need to pay this much money?

My hope would be that we would be doing some of the more basic science work about the pathophysiology of GSM, and I don't see a lot of that.

Patient Care: How do you feel things have the evolution has proceeded since the publication of information countering the WHI interdiction for HRT? How do you see the response among clinicians and women at this point?

Mitchell: I think the first thing is not that anything has countervened WHI. It's just that we are interpreting WHI more specifically. The risk was seen in people who were in their late 60s, early 70s, who started hormone therapy after a long period of not being on hormones. Those are the people with the highest risk, and that was interpreted very broadly when the first study came out, so now I think there is nuance.

For [genitourinary syndrome of menopause], I don't think it matters, because the systemic hormones don't actually have as much of an impact on vulvovaginal symptoms or urinary symptoms as topical estrogen. Actually, systemic hormones can worsen urinary incontinence, whereas topical probably helps.

References

1. Cuccu I, D'Ague TG, Firulli I, et al. Update on geniturinary syndrome of menpause: a scoping review of a tailored, treatment-based approach. Life. 2024;14(11):1504. doi:10.3390/life14111504
2. Cruff J, Khandwala S. A double-blind randomized sham-controlled trial to evaluate the efficacy of fractional carbon dioxide laser therapy on genitourinary syndrome of menopause. J Sex Med. 2021;18(4):761-769. doi:10.1016/j.jsxm.2021.01.188.
3. Laser for genitourinary syndrome of menopause: what we know and what we need to know. Climacteric. 2025;28:414-422. doi: 10.1080/13697137.2025.2455186
4. Manson JE, Crandall CJ, Rossouw JE. The Women's Health Initiative randomized trials and clinical practice: a review. JAMA. 2024;331(20):1748-1760. doi:10.1001/jama.2024.6542.
5. HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. News release. US Food and Drug Administration. November 10, 2025. Accessed November 18, 2025. https://www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy