Hormone Therapy After the FDA Black Box Removal
November 26, 2025
Hormone Therapy After the FDA Black Box Removal:
What “Appropriate Use” Really Means — And Why Women Deserve Better
By Susan Merenstein, Holistic Consultant Pharmacist
The Vital Health Pharmacist™
When the FDA removed the long-standing boxed warning from menopausal hormone therapy, headlines exploded!
“In its updated labeling, the FDA stated that menopausal hormone therapy is safe when appropriately used — meaning therapy should be individualized based on a woman’s symptoms, risk factors, and treatment goals. The agency specifically emphasized that decisions about hormone type, dose, route, and duration must be tailored to each woman, rather than applied uniformly.”
They do not mean hormones are safe in any dose, for any woman, in any form, or without monitoring.
They mean hormones are safe when used the right way — with individualized, physiology-based care which is what I have been counseling women on for over 25 years.
The FDA’s suggestion that hormone therapy is best limited to women under 60 or within 10 years of menopause is outdated, and the idea that hormones stop being safe after age 60 is absurd! In real practice, women in their 70s and 80s can thrive on physiologic, safely balanced human identical hormones when properly monitored.
NOTE: Now that the FDA has removed the boxed warning, there is a very real concern that many clinicians will return to prescribing Prempro — a drug that still contains medroxyprogesterone acetate (Provera), the same synthetic progestin used in the WHI study. This is where the disconnect lies: the FDA removed the warning, but they did not remove the biochemical reality that Provera is not progesterone.
The hormone therapy that caused the fear in 2002 was the combination of oral conjugated equine estrogens (CEE) plus Provera — not bioidentical estradiol and not bioidentical progesterone.
How did we get here? Here is a short 101 hormone history lesson:
Premarin, derived from Pregnant Mare Urine was marketed for decades since the 40’s and promoted as a 'stay young forever' drug. But by the 70s, research showed that unopposed estrogen dramatically increased endometrial cancer risk. Instead of switching to bioidentical progesterone which has been around since 1930, Pharma added the synthetic manmade progestin Provera to counteract that risk. The resulting combination — Prempro — was never evaluated in large pre-market long-term safety trials.
Before 2002, hormone therapy was considered safe, cardioprotective, and beneficial for women. Most women were prescribed Premarin or Prempro, routinely, and often for life.
What most people don’t know is that the Women's’ Health Initiative was designed to test whether Premarin and synthetic Provera could prevent chronic disease in women who were, on average, 63 years old — many more than ten years past menopause. These were not newly menopausal women. And they were not using bioidentical hormones.
*(The women in the Women's Health Initiative (WHI) study were aged 50 to 79 with the average age being 63 years old. At the time of enrollment in the 1990s, all participants were postmenopausal.)
As such, when discussing risk/benefit results, it is more precise to say ‘progestin/progestogen’ when referring to that historical data, and reserve ‘progesterone’ when referring to natural or bio-identical progesterone molecules.”
And let’s be honest: after the WHI findings were released, Wyeth Ayerst (later Pfizer) lost billions in Prempro sales — so the removal of the boxed warning creates a renewed market opportunity for a drug that still uses the same synthetic progestin that caused the original concerns. Until the FDA explicitly distinguishes progestins from progesterone, confusion will persist — and women deserve far better clarity, transparency, and individualized care.
Since 2020, we’ve seen a sharp rise in both compounded BHRT and FDA-approved bioidentical hormone therapy. Telehealth expansion, a wave of menopause education, and growing distrust of synthetic progestins pushed millions of women toward individualized, physiology-based care. Current estimates suggest 3–4+ million U.S. women now use compounded bioidenticals, with another 4–6 million using FDA-approved estradiol and progesterone. Much of this growth reflects women rejecting the CEE + Provera combination used in WHI and choosing personalized, transdermal, multi-hormone regimens instead. This post-2020 acceleration underscores how deeply the WHI backlash reshaped women’s choices and the demand for evidence-based, individualized therapy.
Unfortunately, many women never receive “appropriate use” because most clinicians were never taught how to:
- Balance bioidentical hormones
- Treat perimenopause
- Dose physiologically
- Use transdermal routes safely
- Interpret saliva or capillary testing
- Recognize testosterone overdosing
- Understand how topical progesterone truly works
And importantly — few were taught the fundamental difference between progesterone and progestins. These molecules behave differently in breast tissue, cardiovascular tissue, the brain, and the endometrium. Synthetic progestins like MPA have known adverse vascular effects, while bioidentical progesterone shows neutral or beneficial effects. Yet they are still conflated in mainstream medicine, research articles, and even high-profile expert commentary.
This lack of education has real consequences.
This blog breaks down what appropriate use actually means — and what women must know to protect their health.
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THE REAL PROBLEM: Misinformation, Not Hormones
Very few clinicians were ever trained to use hormones appropriately. Surveys of U.S. OB/GYN residency programs show that most residents receive less than 3 hours of menopause or hormone therapy education in their entire training, and fewer than 10% report having a formal menopause curriculum at all. This lack of education is the root cause of most hormone misinformation, misprescribing, and avoidable harm — not the hormones themselves.
Women are not failing therapy; the system is failing women.
Even fewer programs cover:
- Bioidentical vs synthetic hormones
- The biochemical difference between a synthetic mimicry progestin and human produced progesterone
- Transdermal delivery and improved safety profiles
- The role of capillary and saliva testing
- Testosterone use in women
- Perimenopause physiology
- Endometrial protection with topical progesterone
Meanwhile, social media “experts,” influencers, and online clinics promote information that ranges from incomplete…to blatantly incorrect.
Women are left confused — or harmed.
This confusion is made worse when prominent voices fail to clearly differentiate progesterone from synthetic progestins. This is more than semantics — it changes the risk/benefit profile entirely. The WHI findings that shaped decades of fear were due to Provera, not progesterone. Yet many articles (including Dr. Attia’s) still use the terms interchangeably, reinforcing outdated misunderstandings.
What “Appropriate use” really means
Safe hormone therapy depends on getting all six pieces correct:
- Right Woman
Individualized evaluation — symptoms, risks, genetics, history. - Right Hormone
Bioidentical estradiol, progesterone, testosterone, and DHEA.
Not synthetic progestins such as MPA/Provera, which carry different risk profiles entirely. Misunderstanding the difference between progesterone and progestins leads to inappropriate decisions around “balance,” “endometrial protection,” and safety — another area where proper education is essential. - Right Dose
Physiologic doses — not supraphysiologic, not pellet-level megadosing. - Right Route
Transdermal estradiol is safest for cardiovascular health v oral estradiol which can cause an increase in clotting factors. Transdermal Progesterone is a vasodilator. - Right Balance
Estrogen must be balanced with adequate progesterone.
Testosterone must remain in female ranges. - Right Monitoring
The most common point of failure.
Many clinicians use venous serum to monitor transdermal hormones — which do not show up in serum. This leads to wrong doses, wrong conclusions, and avoidable harm.
Let’s look at a real example.
A real client example: when “appropriate use” failed
A woman called me at my pharmacy recently — frightened, angry, and confused.
She had been prescribed a bioidentical estradiol patch with too little oral bioidentical progesterone (filled at another compounding pharmacy).
And, she never took a “hormone holiday”. I always counsel my clients to put the patch on Monday, Tuesday, and Wednesday, change for Thursday, Friday, and Saturday, and take a “receptor break” on Sundays. We don’t produce hormones daily in our bodies!)
The outcome?
- Endometrial hyperplasia
- Stage 1 endometrial cancer
- Physician Recommendation: hysterectomy and oophorectomy (just to be sure because as she was told by her surgeon and I quote: “a woman your age doesn’t need her ovaries.”)
Her heartbreaking question:
“Where were you then?”
My answer:
I have been here for 25 years! I am so sorry this happened to you!
She didn’t fail hormone therapy.
Her hormone therapy failed her — because it wasn’t appropriately prescribed or monitored.
And importantly:
Topical (transdermal) progesterone CAN protect the endometrium — when monitored correctly.
This is not opinion — it’s demonstrated by:
- Dr. Helene Leonetti (2003) — topical progesterone has clear anti-proliferative effects on estrogen-stimulated endometrium.
- Dr. David Zava / ZRT — serum drastically under-reflects progesterone delivered through the skin; saliva and capillary show true tissue uptake.
- Dr. Kenna Stephenson — in a multi-year outcomes project (CHOIICE study), individualized compounded BHRT including transdermal progesterone showed favorable changes in cardiovascular and inflammatory biomarkers and improved quality-of-life (IJPC 2013).
This body of evidence reinforces the essential point missing from WHI-era interpretations — progesterone supports safety; progestins created the risks that terrified women. They are not interchangeable.
The confusion arises because…
Serum shows very little topical progesterone “being absorbed”
Saliva and capillary blood reflect true tissue levels
If you test the wrong bodily fluid → you get the dose wrong → and the wrong outcome.
Why Salivary and Capillary Blood Testing are superior
Hormones are lipophilic. (Fat loving)
Serum is hydrophilic. (Water loving)
Estradiol, progesterone, and testosterone move into:
- fatty tissues
- cell membranes
- salivary glands
- capillary beds
- red blood cell membranes
They do not accumulate meaningfully in watery venous serum
Serum appears falsely low
Saliva shows bioavailable hormone
Capillary whole blood shows tissue-delivered hormone
This is why:
- Women overdosed on testosterone “look normal” in serum
- Progesterone creams “look like they don’t absorb” in serum
- Estradiol patches “look too low” in serum
- Practitioners raise doses unnecessarily
This is not hormone failure — it’s testing failure.
It is also why expert commentary relying solely on serum labs (including recent podcasts, articles, and online clinical programs) continues to misinterpret real-world pharmacology/biochemistry of bioidentical hormones.
And speaking of testing failures, I will be covering thyroid hormone and testing in my next blog!
Hormone needs vary by life stage-what’s safe and appropriate in:
Pre-menopause:
– Cyclical symptoms, PMS/PMDD, PCOS, heavy bleeding → progesterone support, cycle mapping, stress axis.
- Young women may be put on birth control for many years to supposedly “balance” hormones. (one client I have was on BC pills for 35 years!)
Perimenopause:
– THE most mismanaged and mistreated phase.
– Fluctuating estrogen, declining progesterone, anovulatory cycles.
– Low-dose transdermal estrogen + adequate progesterone can be life-changing.
– Women need nervous system regulation, stress and sleep support .
– Lisa Mosconi, PhD (Weill Cornell) and others show that the female brain begins to shift metabolically during perimenopause — the earliest measurable changes associated with Alzheimer’s risk.
Post-menopause
The first 10 years after menopause represent a critical therapeutic window for protecting cognitive and bone health.
Bone protection:
– Estrogen loss accelerates bone loss up to 10% in first 5 years postmenopause without estradiol and increases fracture risk.
– Estradiol therapy stabilizes bone turnover and reduces fractures long-term.
– Progesterone helps stimulate new bone formation.
Brain health:
*Neuroprotection & the “Critical Window” Theory
– Estradiol supports brain metabolism and reduces Alzheimer’s risk when started early.
– Estradiol is profoundly neuroprotective.
It supports:
• synaptic density
• glucose metabolism in the brain
• mitochondrial energy production
• reduced neuroinflammation
• antioxidant protection
Progesterone’s role:
- Progesterone supports myelination, calming neurotransmission, and repair mechanisms in the brain.
- The combination of estradiol + progesterone appears to be more neuroprotective than either hormone alone.
Post-hysterectomy
- Progesterone supports brain, sleep, calmness — not just the uterus!
The idea that women without a uterus ‘don’t need progesterone’ is misguided; progesterone still supports sleep, anxiety relief, and vasodilation, and remains an important part of the hormone symphony.
Test and individualize therapy!
Special Populations and hormone needs
Breast Cancer Survivors
- Vaginal estrogen safe for nearly all women. (NAMS, ACOG, ASCO)
- Systemic therapy requires individualized care.
- Progesterone’s protective effects on the breast tissue and balancing estrogen and stress response are crucial.
Cardiovascular Disease
- Transdermal estrogen = lowest clot risk
- Oral estrogen = increases clot/stroke risk
- Micronized progesterone = cardio-neutral and a vasodilator (Dr. Kenna Stephenson)
*Alzheimer’s Prevention
- Early estrogen therapy provides neuroprotection (“critical window theory”-Lisa Mosconi PhD)
ALWAYS balance ALL estrogen therapy with progesterone!
Key Takeaways
- Hormones are safe. Mismanagement is dangerous.
- “Appropriate use” means individualized, physiology-based therapy.
- Topical progesterone does protect the endometrium — when correctly monitored.
- Never use male-dose testosterone in women.
- Use the correct monitoring medium (saliva/capillary blood).
- Women deserve accurate information and expert guidance.
And we must always distinguish progesterone from progestins, because the risks associated with synthetic progestins have been wrongly attributed to all progesterone for over 20 years. - To quote Dr. Kenna Stephenson in her interview about her *CHOIICE Study:
- “We need to treat women’s hormone problems not just with one hormone (e.g. estradiol or progesterone) but with the hormones a woman needs based on symptoms and testing. Some women need only estrogens and/or progesterone, others need to add DHEA or Testosterone.”
- David Zava PhD further adds: “It’s absurd that clinical studies mostly are monotherapy based, so far removed from how practitioners treat their patients with polyhormone therapy as it should be, if needed. Its the symphony of hormones all creating the beautiful music of health and longevity”.
These findings make one thing unmistakably clear: when any human-identical hormone is prescribed physiologically, balanced appropriately, and monitored correctly, hormone therapy becomes a safe, transformative, and profoundly effective tool for women’s health.
If you’d like to explore the science and history behind the WHI findings that shaped two decades of fear, I’ve written an addendum that breaks down the facts, myths, and what the data truly shows — in plain language.
“Addendum: WHI Facts, Myths & Science”
And because so many women are now turning to telehealth for help, I’ve also created a separate article on the surge of online testosterone prescribing, who it helps, and where it can go very wrong. These two companion pieces complete the conversation around “appropriate use” and help protect women from confusion, misinformation, and over-prescribing.
“The Truth About Online Testosterone Prescribing for Women”.
REFERENCES
Leonetti HB, Wilson KJ, Anasti JN.
Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium.
Fertility and Sterility. 2003;79(1):221–222.
Du JY et al.
Percutaneous progesterone delivery via cream or gel: evaluation using serum, whole blood, saliva, and capillary blood.
Menopause. 2013;20(11):1169–1175.
*Stephenson K, Neuenschwander PF, Kurdowska AK, Zava DT, Pinson B, Price C.
The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors, cardiovascular biomarkers, quality-of-life measures, and health outcomes in perimenopausal and postmenopausal women.
International Journal of Pharmaceutical Compounding. Jan/Feb 2013:74–85.
Stephenson K et al.
Transdermal progesterone: effects on menopausal symptoms and thrombotic, anticoagulant, and inflammatory factors.
International Journal of Pharmaceutical Compounding. 2008;12(4):295–304.
Stephenson K, Jones B, Stephenson D. The role of drug promotion in hormone replacement therapy prescribing in the United States. International Journal of Pharmaceutical Compounding. 2006;10(3):175-184.
Stephenson K. The salivary hormone profile in the clinical evaluation of women. International Journal of Pharmaceutical Compounding.2004;8(6):427-435.
Du JY, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized crossover study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause. 2013 Nov;20(11):1169-1175.
Zava DT. Topical therapy with estradiol, progesterone, and testosterone and their distribution in saliva, capillary blood, serum, and urine. Townsend Letter. Jan 2021.
Zava DT et al. Percutaneous absorption of progesterone. Maturitas. 2014; (S0378-5122(13)00316-2).
NAMS 2022 Hormone Therapy Position Statement.
Menopause.
ACOG Clinical Consensus & ASCO Guidelines on GSM management.
Canonico M, Scarabin PY.
Transdermal estrogen & cardiovascular safety. Circulation, BMJ.
Maki PM, Henderson VW.
Estrogen and brain aging. Endocrine Reviews.