Menopausal hormone therapy: what the 2025-26 labeling change removes and what it keeps

Menopausal hormone therapy (MHT) is systemic or vaginal estrogen, with or without a progestogen. On 10 November 2025, the FDA announced it was asking application holders to remove cardiovascular disease, breast cancer and probable dementia language from the boxed warning on these products ^[1]. A JAMA Viewpoint by FDA authors, published 13 January 2026, described the agency's intended label updates ^[2]. On 12 February 2026, the FDA reported approving the first labeling changes for six products, which removed those three risk statements from the boxed warning ^[3].

What did the labeling change remove, add and keep?

The FDA drug alert lists further requested changes ^[4]:

• Endometrial cancer: the agency keeps this boxed warning for systemic estrogen-alone products and requests removal from all others ^[4].
• Dose and duration: the FDA asks to delete the lowest-effective-dose, shortest-duration statement ^[4].
• Timing: for systemic products, the agency asks for added consideration of therapy for moderate to severe vasomotor symptoms in women under 60 or within 10 years of menopause ^[4].
• Vaginal products: for local vaginal estrogen products, the FDA asks for condensed safety information that prioritizes what is most relevant to the local vaginal formulation ^[4].
• Retained: the FDA keeps cardiovascular and breast cancer warnings in the body of systemic product labeling ^[4].

What do the randomized trials show?

The 2026 Cochrane update included 24 randomized trials with 45,660 participants, but its main results come from one study with two concurrent hormone therapy arms: 16,608 women with a uterus on combined therapy and 10,739 women after hysterectomy on estrogen alone ^[5]. In the Cochrane analysis of combined estrogen plus progestin, breast cancer risk was probably raised (RR 1.27, 95% CI 1.03 to 1.56) and coronary events probably did not differ (RR 1.17, 95% CI 0.95 to 1.44) ^[5]. For estrogen alone, the Cochrane authors found probably little to no difference in breast cancer risk (RR 0.79, 95% CI 0.61 to 1.01) or coronary events (RR 0.94, 95% CI 0.78 to 1.13) ^[5]. The Cochrane update found stroke risk may be raised with combined therapy (RR 1.39, 95% CI 1.09 to 2.09; low certainty) and was probably raised with estrogen alone (RR 1.33, 95% CI 1.06 to 1.67; moderate certainty) ^[5]. Combined therapy may also raise venous thromboembolism risk (RR 2.03, 95% CI 1.55 to 6.64; low certainty) ^[5].

How do age and timing change the picture?

A 2024 JAMA review of two large randomized hormone therapy trials in postmenopausal women reported lower rates of adverse effects when therapy began in early rather than later menopause ^[6]. The same review concluded that the trials do not support hormone therapy to prevent cardiovascular disease, dementia or other chronic disease ^[6]. The FDA alert notes that the probable dementia findings came from trials enrolling women aged 65 to 79 ^[4].

Where is the evidence uncertain?

Only about 30% of trial participants in the Cochrane update were aged 50 to 59 at baseline ^[5]. The Cochrane update's main results come from one study of oral therapy, which may not represent formulations in current practice ^[5]. A December 2025 meta-analysis of ten studies (nine observational) with 1,016,055 participants found no significant association between MHT and mild cognitive impairment or dementia, with certainty of evidence from moderate to very low ^[7]. A 2026 Obstetrics & Gynecology article argues that the 2003 warnings were generalized across all doses and routes, including vaginal therapy ^[8].

At the point of care: what to check

• Age and years since menopause: whether the patient is under 60 or within 10 years of menopause, the thresholds in the FDA's requested systemic labeling changes ^[4].
• Uterine status, since the FDA alert keeps the endometrial cancer boxed warning for systemic estrogen-alone products ^[4].
• Systemic or local vaginal product, since the FDA's requested labeling changes differ between them ^[4].
• Combined or estrogen-alone therapy, since the Cochrane review found different risk profiles: combined therapy probably raised breast cancer risk and may have raised stroke and venous thromboembolism risk, while estrogen alone probably made little to no difference to breast cancer risk but probably raised stroke risk ^[5].