What if the estrogen missing from your hormone therapy wasn’t left out because it failed, but because no one could build a profitable drug around it?
Your body naturally produces three estrogens: estrone, estradiol, and estriol. Yet most hormone therapy replaces only estradiol. It is easy to assume that estriol was studied, found ineffective, and discarded. But that is not what happened. It didn’t necessarily lose a scientific argument; it lost a business one, and over time, we mistook that silence for proof.
That missing conversation matters because estrogen does not produce the same effect everywhere in the body. And this could help explain why some women see their hot flashes disappear on estradiol while continuing to struggle with mood changes, disrupted sleep, brain fog, gut problems, recurrent UTIs, or unexplained inflammation. Their treatment may not be failing; it may simply be addressing only part of the hormonal picture.
In this episode, I talk about why you never hear about estriol, why it’s not about effectiveness, and when to consider asking your doctor about it.
What You'll Discover In This Episode
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Why your body produces three estrogens, while most hormone therapy replaces only one
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How estriol may have lost a business argument, not a scientific one
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Why the absence of an FDA-approved estriol product does not automatically prove that estriol is ineffective
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The crucial difference between a hormone binding to a receptor and fully activating it
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How estrogen receptor alpha and estrogen receptor beta can produce very different effects throughout the body
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Why estradiol can successfully relieve hot flashes while mood, sleep, memory, gut, or inflammatory symptoms remain
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What research involving the brain, gut, immune system, and urogenital tissue suggests about receptor beta
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What human multiple sclerosis trials may reveal about estriol’s potential immune effects, and what those studies cannot yet prove
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Why elevated cholesterol and metabolic health may further complicate estrogen receptor signaling
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The strongest scientific objections to combination hormone therapy—and why they deserve serious answers
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Why estriol being a “weaker” estrogen may be a feature in some formulations, not necessarily a flaw
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How poorly timed blood tests can make a compounded hormone cream appear ineffective
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What to ask your provider if your current estrogen therapy is helping, but you still do not feel like yourself
PS. If you enjoy the show, remember to leave a review on your favorite podcast app! Reviews help the podcast reach a wider audience and help more people.
Research Referenced in This Episode
Every study below includes a PubMed ID (PMID), which you can use to find the original paper at PubMed.
This episode discusses hormone therapy for educational purposes only. It is not medical advice or a substitute for a conversation with your healthcare provider about your symptoms, medical history, and treatment.
Estrogen Receptor Biology
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Binding affinities of 74 naturally occurring estrogen metabolites at estrogen receptors alpha and beta. Estriol demonstrated preferential binding to ERβ.
Zhu BT, et al. Endocrinology. 2006. PMID: 16728493 -
Comparative transcriptional activity of estradiol at ERα and ERβ.
Bhavnani BR, et al. Endocrinology. 2008. PMID: 18599548 -
Crystal structure research examining how estradiol interacts with ERβ.
Souza PCT, et al. Scientific Reports. 2017. PMID: 28615710 -
27-hydroxycholesterol as a negative allosteric modifier of estradiol binding at ERβ.
Starkey NJE, et al. Endocrinology. 2018. PMID: 29579190
Brain, Mood, and Memory
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Effects of an ERβ-selective agonist and estradiol on serotonergic neurons after ovariectomy.
Suzuki H, et al. Molecular Psychiatry. 2013. PMID: 22665260 -
Antidepressant effects of estradiol and an ERβ-selective agonist after long-term ovarian hormone deprivation.
Hou Y, et al. Journal of Psychiatry & Neuroscience. 2019. PMID: 30565903 -
Effects of ERβ activation on synaptic proteins, hippocampal signaling, and memory performance.
Liu F, et al. Nature Neuroscience. 2008. PMID: 18297067 -
Estriol treatment, cortical atrophy, remyelination, and neuronal preservation.
Meyer CE, et al. Laboratory Investigation. 2023. PMID: 37245852 -
ERβ-mediated neuroprotection independent of peripheral anti-inflammatory effects.
Tiwari-Woodruff S, et al. Proceedings of the National Academy of Sciences. 2007. PMID: 17785421
Gut Health
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Effects of ERα- and ERβ-selective agonists and estradiol on intestinal cell proliferation and apoptosis.
Schleipen B, et al. Carcinogenesis. 2011. PMID: 21856997 -
The role of ERβ in intestinal tight junctions and gut permeability.
Braniste V, et al. American Journal of Physiology—Gastrointestinal and Liver Physiology. 2011. PMID: 21252046 -
How the gut microbiome and the estrobolome influence circulating estrogen.
Baker JM, et al. Maturitas. 2017. PMID: 28778332
Estriol and the Immune System
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Immune markers in postmenopausal women receiving oral estradiol.
Itaborahy RM, de Medeiros SF. Climacteric. 2016. PMID: 27593223 -
Estriol treatment and changes in inflammatory and anti-inflammatory immune signals in women with multiple sclerosis.
Soldan SS, et al. Journal of Immunology. 2003. PMID: 14634144 -
Estriol-generated tolerogenic dendritic cells in an autoimmune model.
Papenfuss TL, et al. Journal of Immunology. 2011. PMID: 21317386 -
Estriol and pulmonary inflammatory gene expression during influenza infection.
Vermillion MS, Ursin RL, Klein SL, et al. Endocrinology. 2018. PMID: 30032246 -
Estriol regulation of TNF and IL-6 responses in a murine endotoxemia model.
Zuckerman SH, et al. Inflammation. 1996. PMID: 8979148 -
Review of estriol’s immunomodulatory role across multiple sclerosis and other immune-mediated conditions.
Ali E, Mangold C, Peiris AN. Menopause. 2017. PMID: 28375935
Human Clinical Trials of Estriol
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Phase I trial of oral estriol in women with relapsing-remitting multiple sclerosis. Inflammatory brain lesions decreased during treatment, returned after withdrawal, and decreased again when treatment resumed.
Sicotte NL, et al. Annals of Neurology. 2002. PMID: 12436153 -
Phase II randomized, placebo-controlled trial of estriol added to standard therapy in 164 women with relapsing-remitting multiple sclerosis.
Voskuhl RR, et al. The Lancet Neurology. 2016. PMID: 26621682
Estriol Physiology and Ovarian Function
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Ovarian transplantation and immune function in post-reproductive mice.
King A, et al. Frontiers in Endocrinology. 2023. PMID: 36755910
Route of Administration and Inflammation
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Changes in C-reactive protein among postmenopausal women using different hormone preparations in the PEPI trial.
Circulation. 1999. PMID: 10500035 -
Effects of oral and transdermal estradiol on C-reactive protein and other inflammatory markers.
Zegura B, et al. Atherosclerosis. 2003. PMID: 12732395
An Important Note About the Evidence
This research includes receptor pharmacology, animal studies, and human clinical trials conducted in specific patient populations, most notably women with multiple sclerosis. These different forms of evidence cannot automatically establish that estriol will produce the same benefits for every woman using menopausal hormone therapy.
There is currently no large randomized controlled trial directly comparing estradiol alone with combined estradiol-and-estriol therapy in postmenopausal women. There is also no equivalent trial establishing that estradiol alone replaces everything women may lose when natural production of all three estrogens declines.
The purpose of sharing this research is not to present estriol as a miracle or to suggest that women who are doing well on estradiol should change their treatment. It is to show why the scientific conversation remains open—and to give women and their healthcare providers the sources they need to examine the evidence for themselves.