Menopausal Hormone Therapy in 2025: Why Dose, Formulation, and Delivery Matter
Medically Reviewed By: Dr. Lisa Larkin
Date: 11/17/2025
The Conversation Around Menopause Is Changing
For more than twenty years, both local vaginal formulations and systemic formulations of menopausal hormone therapy (MHT) carried the same boxed warning, signaling risks for stroke, blood clots, dementia, and breast cancer. This boxed warning was added in the early 2000’s based on data from the WHI study of one specific systemic formulation of MHT. This boxed warning has shaped decades of fear and confusion for women and their clinicians.
In 2025, that narrative is evolving. The FDA and leading experts are re-examining how menopausal hormone therapy is labeled, prescribed, and understood. The science shows that local vaginal hormone therapy and systemic hormone therapy are different, and menopause management is not a one-size-fits-all approach. Hormone therapy options today are very different from the therapies studied more than twenty years ago, and our understanding of risk and benefit and the nuance in prescribing has grown more sophisticated.
The conversation now centers on a simple truth: dose, formulation, and delivery method matter, and so do individual patient factors, such as age, time since menopause, and overall health.
The FDA Mandated Boxed Warning
The original black box warning dates to the Women’s Health Initiative (WHI), a landmark study that examined one specific formulation of hormone therapy: conjugated equine estrogen (CEE), often paired with a synthetic progestin. The participants were, on average, well past menopause, and the therapy doses were high compared with modern standards.
The findings of that single trial were applied to every form of estrogen, regardless of type, dose, or route of delivery. As a result, millions of women and clinicians backed away from hormone therapy entirely.
The Path to Removing the Boxed Warning
For more than a decade, experts, professional societies and advocacy groups have been pushing the FDA to remove the boxed warning on local vaginal therapy- unsuccessfully. Recently, the enormous interest in menopause, growing social media messaging and passionate physicians advocating in the space led to the change.
In July 2025, thanks to the work of many, the FDA held an advisory committee to review the existing class labeling for menopausal hormone therapy. The panel recommended that the boxed warning be removed or revised for low-dose vaginal estrogen, recognizing that its systemic absorption, and therefore its risk profile, is minimal.
That recommendation signals a broader shift: regulators and clinicians alike are acknowledging that the “estrogen” class label does not apply to every formulation and dose of menopausal hormone therapy.
For providers and patients, this change holds promise for more accurate counseling, fewer misconceptions, and increased access to treatments that can safely enhance the quality of life for women in midlife and beyond.
Not All Estrogens (or Progestogens) Are the Same
One of the most important lessons from this moment is that not all hormones used in menopausal therapy are created equal. Yet for decades, every form of estrogen—no matter the molecule or delivery method, has carried the same warning label. That “class” approach has outlived the evidence.
Systemic vs. Local Therapy
Systemic hormone therapy, including oral tablets, patches, gels, or sprays, circulates estrogen throughout the body. It can help with hot flashes, night sweats, and bone protection, but requires careful monitoring of breast and uterine effects.
Local (vaginal) estrogen therapy works directly on vaginal and urinary tissues to relieve dryness, discomfort, and urinary urgency associated with genitourinary syndrome of menopause (GSM). Because only trace amounts reach the bloodstream, it has a very different risk profile. Experts now agree that these local products should not carry the same boxed warning as systemic therapies.
Conjugated Equine Estrogen vs. Estradiol
The WHI trial used conjugated equine estrogen (CEE), a mixture derived from the urine of pregnant mares. Estradiol, on the other hand, is chemically identical to the primary estrogen made by the human body. Modern menopausal therapies increasingly use estradiol because it provides more physiologic replacement at lower doses. Treating these two compounds as identical overlooks their distinct effects on clotting, cholesterol, and breast tissue.
Estradiol vs. Ethinyl Estradiol or E4
Ethinyl estradiol is a potent synthetic estrogen long used in birth control pills, while E4 (estetrol) is a newer molecule with selective receptor activity. Their potencies, half-lives, and systemic effects differ significantly from those of natural estradiol. When all are grouped under one “estrogen” label, nuance and safety distinctions are lost.
Progesterone vs. Progestin
Progesterone, bio-identical to what the body naturally produces, acts differently from synthetic progestins used in some hormone therapies and contraceptives. Progestins vary in their effects on mood, lipids, and breast tissue. For many women, micronized progesterone provides a safer and better-tolerated alternative to estradiol.
Why These Distinctions Matter
When every product carries the same warning, patients and clinicians lose sight of crucial differences:
A woman using a low-dose vaginal estradiol insert should not be counseled as though she were taking high-dose oral CEE.
A clinician prescribing micronized progesterone should not have to rely on data from synthetic progestins.
And no woman should be led to believe that “hormone therapy” means a single, uniform product.
Menopausal hormone therapy in 2025 demands precision: matching the right molecule, dose, and route to the individual patient.
What This Means for Women and Providers
As the FDA re-evaluates labeling, we are entering a period of both opportunity and responsibility.
For women: this means greater access to safe, effective options for managing menopausal and post-menopausal symptoms, without unnecessary fear. If you have struggled with vaginal dryness, urinary discomfort, or painful intimacy, ask your provider whether a local therapy might help.
For providers: this is a call to update counseling and prescribing practices. Distinguish local from systemic therapies, educate patients on molecular differences, and emphasize that timing, dose, and delivery matter as much as the decision to start therapy itself.
Shared decision-making, informed by up-to-date evidence, remains a central principle. The goal is not to put every woman on hormones, but to help each woman find the right balance for her health and quality of life.
Why This Matters for Ms.Medicine
At Ms.Medicine, our network of clinicians has long championed personalized, evidence-based care for women. The FDA’s evolving position on hormone therapy affirms what we have always believed: women deserve clarity, not confusion.
The removal of outdated warnings is more than a regulatory change; it’s an opportunity to reclaim confidence in midlife care. As the science evolves, Ms.Medicine providers remain committed to translating evidence into individualized treatment plans that prioritize safety, symptom relief, and whole-person wellness.
Because when it comes to hormone therapy, route matters, formulation matters, dose matters, and you matter.
