Prof. Rhonda Voskuhl, M.D.
University of California, Los Angeles (UCLA)
Neurologist, UCLA Comprehensive Menopause Program
Inventor and Founder, CleopatraRX
November 11, 2025
Dr. Makary, the FDA Commissioner, made a major move this week regarding hormone replacement therapy (HRT) for menopausal women. This was long awaited after years of women’s health groups advocating that the black box warning on the label of FDA approved HRTs needs revision. It was done in an unconventional style, consistent with that of the new administration under HHS Secretary, Robert F. Kennedy Jr.
The black box warning was justifiably removed from low-dose vaginal estradiol which has local benefits on vaginal and urinary linings, without reaching significant concentrations in blood to reach breast, heart, brain or bones. Surprisingly, the black box warning was also removed from all estrogens and progesterones, even those that reach the bloodstream in significant amounts because they are given as transdermal patches, creams, or pills. It was shocking to see no distinction made between local exposure versus whole body exposure when considering risk for breast cancer, cardiovascular disease, and thromboembolic disease, each previously observed in relatively older women.
Also surprising was the process. This serious issue for women that has taken decades to get addressed, yet the established process was not used here. An FDA appointed expert review panel convened for 2 hours on July 17, 2025. It applauded the FDA’s attention to this issue, emphasized reasons to remove the black box warning from low-dose vaginal estrogen, and made a distinction between local versus other deliveries of estradiol. This is not the “conventional” process for an FDA decision. The established process is to create an FDA Advisory Committee of independent experts who evaluate and debate the science, have public engagement and transparency, then vote on their recommendation to the FDA.
The American College of Obstetricians and Gynecologists (ACOG) weighed in on the FDA ruling. “Hormones delivered as patches or pills that reach the blood carry more risks. Also, a discussion for 2 hours by a panel in July should not be considered an adequate substitute for an FDA Advisory Committee. When Dr. Makary was asked why the agency chose against an Advisory Committee here, he said “because they are bureaucratic, long, and often conflicted and very expensive”. His FDA “is doing expert panels instead, which are less strict and can be more spontaneous and remain robust.” So, after waiting decades for FDA action, women now get a short cut that saves money.
The position statement of The Menopause Society says that it agrees with the removal of the black box warning for low-dose vaginal estrogen since it likely deterred use of a safe treatment for genitourinary symptoms. However, systemic estrogen still comes with potential risks that should be reviewed in detail when starting therapy, including preference for relatively younger, healthier menopausal women.
Will the FDA’s decision to remove the black box warning from all menopausal hormone types and deliveries send the wrong message to the public? Do women follow the science demonstrating that age of initiation, type and dose of hormone, and delivery method matter? Will they get it that estrogens are not all alike, now that the FDA made no distinctions between them?
The HRT field is unique, and not in a good way. Initially up to the late 1990s, many eligible women took standard systemic HRT using estradiol. After risks were shown in the early 2000s, the pendulum swung to the opposite direction with less than 5% being treated by the mid-2020s. Now, the pendulum will likely swing back to the late 1990s given the removal of the black box warning on all hormones. Will systemic estradiol be safe this time? Why can’t insights gained over decades direct the pendulum to a happy medium? Defying convention and short-cutting the established process is not the answer. Menopause treatment will ultimately be a concern for half the population. It warrants the time and money required to make rigorous decisions that include distinctions between hormone types, doses, and deliveries, and these decisions should carry the full weight of a full FDA Advisory Committee.
Looking forward beyond decades of past debates about estradiol, menopause treatments need to move to estrogen receptor specific targeting to maximize efficacy and minimize toxicity, as pharmaceuticals for other conditions have done. Through all the conflicting clinical reports about estradiol and breast cancer risk, the biological facts remain. Estradiol binds strongly to estrogen receptor alpha in breast. This receptor is associated with breast cancer. Treatments for breast cancer block it. Tamoxifen prevents the body’s estradiol from binding to estrogen receptor alpha in breast, and aromatase inhibitors prevent the body from making estradiol that binds to estrogen receptor alpha in breast. Since breast cancer is common, a different HRT is needed with minimal binding to estrogen receptor alpha in breast.
There is a window of opportunity on the horizon. A different receptor, namely estrogen receptor beta in brain, has been published in numerous scientific papers by numerous groups to be brain protective during aging and in some neurological diseases. An estrogen different than estradiol, namely estriol (oral), binds primarily to this promising estrogen receptor beta in brain (to maximize efficacy), while binding weakly to estrogen receptor alpha in breast (to minimize toxicity). Estrogen receptor specific targeting is the next generation HRT. Future HRTs must maximize efficacy for treatment of cognitive issues of menopause, “HRT Plus” (the brain), with a menu of other HRTs optimized for bone, heart, metabolism, and skin. All without putting breast at risk.
In conclusion, ultimately half the population needs a better option than FDA approved estradiol with no black box, but limited to younger women closer to menopause onset. Why? Each woman will be estrogen deficient for a third of her life, her early 50s to mid-80s, and this is bad her brain, heart, metabolism, bones, and skin.